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Intraductal papillary mucinous neoplasm (IPMN) has been associated with a high incidence of extrapancreatic malignancies (EPMs). However, it is controversial whether IPMN is prognostic for EPM. We aimed to help clarify the issue studying this association in patients with histologically proven IPMN. We reviewed 51 surgically resected IPMNs in Saitama Medical Center, Jichi Medical University between January 1991 and June 2012. Mean follow-up was 63.7±47.8 months. The observed EPM incidence was compared with the expected incidence of cancer in Japan. Of the 51 IPMNs, 14 were malignant and the rest benign. Seventeen EPMs developed in 15 patients (29.4%), nine of which occurred prior to IPMN diagnosis. For all IPMNs, the standardized incidence ratio (SIR) was significantly increased for the six types of reported EPMs (SIR=2.18, CI=1.31-3.42, P=0.004). Benign IPMNs showed no association with EPMs (SIR=0.92, CI=0.43-1,76, P=0.87). In contrast, malignant IPMNs showed a higher association (SIR=3.83, CI=1.87-7.03, P=0.0009). However, the association was mostly due to the prior EPMs, as removal of metachronous EPMs had no significant effect (SIR=3.63, CI=1.59-7.17, P=0.005). Thus, only malignant IPMNs drive the significant association with prior EPMs, showing a near 4-fold increased incidence compared to the general Japanese population. Histological characterization of IPMNs may offer clinical value for EPM patient management. We hypothesize that these observations may be explained if some patients with EPMs present a higher risk to develop IPMNs (and vice versa), possibly resulting from an uncharacterized multiple cancer predisposition condition.

Regorafenib has shown survival benefits in metastatic colorectal cancer patients who were exacerbated after all standard therapies. Some patients, however, exhibit severe adverse events (AEs) resulting in treatment discontinuation. Therefore, the selection of patients likely to benefit from regorafenib is crucial. Twenty patients were treated with regorafenib for metastatic colorectal cancer; 122 plasma samples were taken from 16 of these patients for monitoring of circulating tumor DNA (ctDNA) in the blood. The treatment response, AEs, overall survival (OS), progression-free survival (PFS) and tumor morphologic changes on CT images were evaluated. KRAS mutant ctDNA was determined using digital PCR. Median PFS and OS were 2.5 and 5.9 months, respectively. Treatment was discontinued because of disease progression (PD) in 10 patients, and AEs in another 10 patients. AEs included hyperbilirubinemia, severe fatigue and skin rash. Hyperbilirubinemia was seen in two patients with multiple bilateral liver metastases, and severe fatigue in another 2 patients with poor performance status (PS). These severe AEs resulted in treatment discontinuation. Ten patients had a median PFS of 2.1 months with AE related discontinuation; PD occurred at 3.5 months (p=0.00334). Four patients exhibited a morphologic response, achieving better PFS times of 3.5, 5.3, 5.6 and 14.2 months. Emergence of the KRAS mutation in ctDNA was observed during anti-EGFR antibody treatment in 3 patients among 11 with KRAS wild-type tumors; it was detectable in the blood prior to radiographic detection of PD. Moreover, the KRAS mutation declined in two patients during regorafenib monotherapy. These patients were re-challenged with anti-EGFR antibody. Patients with extensive multiple liver metastases or poor PS are unlikely to benefit from regorafenib. Patients with a morphologic response will probably benefit from regorafenib with adequate management of other AEs. KRAS monitoring in ctDNA could be useful regarding treatment response and in determining treatment strategy.