Recurrence and Survival After Resection of Small Intraductal Papillary Mucinous Neoplasm-associated Carcinomas (≤20-mm Invasive Component)

Winter, Jordan M.; Jiang, Wei; Basturk, Olca; Mino‐Kenudson, Mari; Fong, Zhi Ven; Tan, Wei Phin; Lavu, Harish; Vollmer, Charles M.; Furth, Emma E.; Haviland, Dana; Klimstra, David S.; Jarnagin, William R.; Lillemoe, Keith D.; Yeo, Charles J.; Castillo, Carlos Fernández‐del; Allen, Peter J.

doi:10.1097/sla.0000000000001319

Cited by 65 publications

(37 citation statements)

References 32 publications

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“…9,10 Although the current cutoff points of ≤2 cm, >2 ≤4 cm, and >4 cm were chosen to be consistent with other gastrointestinal and pancreatic tumors (pancreatic neuroendocrine), the results from the current study suggest that they are statistically sound. In the current study, recursive partitioning was performed to evaluate for tumor diameter cutoff points on 1,551 patients (training set) who had undergone a R0 resection.…”

Section: Discussionmentioning

confidence: 87%

Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma

et al. 2017

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Objective To evaluate and validate the proposed 8th edition AJCC system for T and N staging of pancreatic adenocarcinoma. Summary Background Data Investigators have questioned the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma. Methods Prospective databases at Memorial Sloan Kettering (MSK), Massachusetts General Hospital (MGH), and Johns Hopkins Hospital (JHH) were queried for patients who had undergone resection for pancreatic adenocarcinoma. Patients who underwent a margin-negative (R0) resection, and who had previously undergone pathologic review, were included. Patients were staged according to 7th edition AJCC criteria, as well as the proposed 8th edition system that includes different definitions of tumor size (T) and nodal status (N). The dataset was randomly split into training and test sets. Results 2,318 patients were identified who met inclusion criteria. Recursive partitioning on the training set (n=1,551) identified statistically appropriate cutoffs for tumor size (<2.2cm, ≥4.8cm,) and nodal status (no positive nodes, 1–3 positive nodes, ≥4 positive nodes) that supported the proposed 8th edition changes. Median survival in patients staged as T3, N0 by the 7th edition definitions was different between institutions (median Center 1, 24mo; Center 2, 37mo; Center 3, 29mo; p=0.054). This difference was not observed when patients were staged as T3, N0 by 8th edition criteria. Stage, and stage-specific outcome (7th edition), on the test set revealed a predominance of patients (68%) within the IIB subgroup, and a concordance probability estimate (CPE) of 0.57 for stage-specific survival. When assessed with 8th edition criteria, no stage subgroup had a majority of patients, and the CPE was 0.58. Conclusions The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging. This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy.

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Section: Discussionmentioning

confidence: 87%

Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma

et al. 2017

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“…Rather, the evidence indicates that the disease is more aggressive than most other common cancers. For instance, survival with advanced disease is significantly worse than other cancers (31), and early lesions with microinvasion are more likely to spread and recur (32). Similarly, cytotoxic chemotherapy is less effective in PDAC (4, 5).…”

Section: Discussionmentioning

confidence: 99%

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

et al. 2017

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Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer.

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“…Indeed, recent evidence indicates that most patients with worrisome features who do not undergo pancreatic resection will not progress to death over the next 5 years (9). At the same time, once an invasive cancer arises progression may be rapid (10), and recurrence after resection and diminished survival is common even for patients with small cancers (11). …”

Section: Introductionmentioning

confidence: 99%

Cyst Fluid Telomerase Activity Predicts the Histologic Grade of Cystic Neoplasms of the Pancreas

Hata

Molin

Suenaga

et al. 2016

Clinical Cancer Research

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Purpose Pancreatic cysts frequently pose clinical dilemmas. On one hand, cysts with high-grade dysplasia offer opportunities for cure, on the other hand, those with low-grade dysplasia are easily over treated. Cyst fluid markers have the potential to improve the evaluation of these cysts. Since telomerase activity is commonly activated in malignant cells, we evaluated the diagnostic performance of cyst fluid telomerase activity measurements for predicting histologic grade. Experimental design Telomerase activity was measured using telomerase repeat amplification with digital-droplet PCR in surgically-aspirated cyst fluid samples from 219 patients who underwent pancreatic resection for a cystic lesion (184, discovery, 35 validation) and 36 patients who underwent endoscopic ultrasound fine needle aspiration. Methodological and clinical factors associated with telomerase activity were examined. Results Telomerase activity was reduced in samples that had undergone prior thawing. Among 119 samples not previously thawed, surgical cyst fluids from cystic neoplasms with high-grade dysplasia +/− associated invasive cancer had higher telomerase activity (median [interquartile range], 1158 [295.9–13033] copies/μL of cyst fluid than those without (19.74 [2.58–233.6] copies/μL) (P < 0.001). Elevated cyst fluid telomerase activity had a diagnostic accuracy for invasive cancer/high-grade dysplasia of 88.1% (discovery), 88.6% (validation), and 88.2% (merged). Among cysts classified preoperatively as having “worrisome features”, cyst fluid telomerase activity had high diagnostic performance (sensitivity 73.7%, specificity 90.6%, accuracy, 86.1%). In multivariate analysis, telomerase activity independently predicted the presence of invasive cancer/high-grade dysplasia. Conclusion Cyst fluid telomerase activity can be a useful predictor of the neoplastic grade of pancreatic cysts.

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Recurrence and Survival After Resection of Small Intraductal Papillary Mucinous Neoplasm-associated Carcinomas (≤20-mm Invasive Component)

Cited by 65 publications

References 32 publications

Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma

Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

Cyst Fluid Telomerase Activity Predicts the Histologic Grade of Cystic Neoplasms of the Pancreas

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