Regorafenib is used for hepatocellular carcinoma (HCC), but its response does not last long, partly due to chemoresistance acquisition. We performed a clustered regularly interspaced short palindromic repeats (CRISPR)-based loss-of-function genetic screen and aimed to discover molecules involved in regorafenib resistance in HCC. Xenograft tumors established from Cas9-expressing HCC cells with pooled CRISPR kinome libraries were treated with regorafenib or a vehicle. Sequencing analysis identified 31 genes, with the abundance of multiple guide RNAs increased in regorafenib-treated tumors compared to that in vehicle-treated tumors, including 2 paralogues, LATS2 and LATS1, core components of the Hippo signaling pathway. Notably, all eight designed guide RNAs targeting LATS2 increased in regorafenib-treated tumors, suggesting that LATS2 deletion confers regorafenib resistance in HCC cells. LATS2 knockdown significantly mitigated the cytotoxic and proapoptotic effects of regorafenib on HCC cells. LATS2 inhibition stabilized the Hippo signaling mediator YAP, leading to the upregulation of antiapoptotic Bcl-xL and the multidrug resistance transporter ABCB1. Among 12 hepatoma cell lines, the half maximal inhibitory concentration (IC50) values of regorafenib were positively correlated with any of YAP, Bcl-xL and ABCB1 levels. The inhibition of YAP or Bcl-xL in regorafenib-insensitive HCC cells restored their susceptibility to regorafenib. In conclusion, our screen identified the Hippo signaling pathway as the mediator of regorafenib efficacy in HCC.

Poorly differentiated endocrine carcinoma (PDEC) of the pancreas is a rare and aggressive tumor. First-line treatment is commonly a combination of etoposide and cisplatin, but there is no consensus regarding further treatment recommendations. In this report, we describe a case of pancreatic PDEC treated with gemcitabine as third-line chemotherapy. A 62-year-old man with pancreatic PDEC was administered etoposide plus cisplatin as first-line treatment; he then received irinotecan for tumor relapse. However, because irinotecan induced ileus in this patient, we chose gemcitabine as third-line chemotherapy. After two cycles of gemcitabine (1000 mg/m(2) on days 1, 8 and 15 every 4 wk), a partial tumor response was noted by computed tomography (approximately 68% reduction in tumor size). Our patient survived for 15 mo after diagnosis. This is a rare case of unresectable pancreatic PDEC, which showed a partial response to gemcitabine after the failure of two other regimens. Gemcitabine could be an effective treatment option for pancreatic PDEC that is resistant to other treatments.

Gastrointestinal: Unusual duodenal follicular lymphoma observed by magnifying endoscopy with narrow-band imagingA 77-year-old man was referred to our hospital for a health check-up of the upper gastrointestinal (GI) tract. Conventional esophagogastroduodenoscopy revealed an elevated lesion in the superior duodenal angulus ( Figure 1A). The lesion was irregularly shaped, showed an ill-defined border, and was partially covered with an irregular surface and tiny red spots. After indigo carmine was sprayed on the surface, some nodules were visualized at the border of the elevated lesion ( Figure 1B). Endoscopy with narrowband imaging (NBI) clarified enlarged villi at the surface of the elevated lesion ( Figure 1C). Magnifying endoscopy with NBI revealed irregular microvessels on the surface of each nodule ( Figure 1D). Hence, we thought the elevated lesion could be a nonepithelial tumor such as follicular lymphoma (FL).Biopsy specimens were obtained under NBI magnifying observation for further evaluation. Histological examination of these specimens confirmed the diagnosis of FL, grade 1 (Figure 2). Immunohistochemical staining was positive for CD20, CD10, and bcl-2. The patient was diagnosed with duodenal FL (stage I, according to the Lugano classification). He declined chemoimmunotherapy and chose watchful waiting.GI-FL is rare, accounting for 1%-3.6% of GI non-Hodgkin's lymphoma. The most common site of GI-FL is the duodenum, followed by the ileum and jejunum. Endoscopy shows primarily small whitish polypoid or nodular lesions, which are confluent or scattered. However, the remaining endoscopic findings are uncommon. An elevated lesion with nodules on only a part of the surface, as in our patient, is not typical. Reports and case series of GI-FL observed by magnifying endoscopy with NBI are increasing, and magnifying endoscopy with NBI of duodenal FL has detected coiled and elongated microvascular patterns within the surface of the lesions and opaque white spots under the microvessels.If a unique elevated lesion is found in the duodenum, FL should be considered as a rare differential diagnosis. Observation of the lesion in detail by using magnifying endoscopy with NBI and acquisition of biopsy specimens are important for accurate diagnosis. Contributed by

Spontaneous splenic rupture is a life-threatening disease and an important differential diagnosis of acute abdomen. Early clinical diagnosis and rapid intervention is required to ensure patient survival. Spontaneous splenic rupture may be induced by hematological, inflammatory or infiltrative diseases affecting the spleen. Splenomegaly may also significantly increase the risk of rupture. Other contributory factors include male, adulthood, rapid growth of the spleen and splenic abscess. Here, we present the case of a 69-year-old man who was undergoing chemotherapy for B-cell chronic lymphoid leukemia. He was admitted to our hospital after he suddenly developed persistent upper abdominal pain. Computed tomography and ultrasonography revealed accumulation of free fluid in and around the spleen. He was diagnosed as having spontaneous splenic rupture and an emergency operation was performed. During the operation, we found a massively enlarged spleen with several capsular tears, and performed a splenectomy. The patient made a good recovery. Pathological examination revealed that the spleen was infiltrated by CD20-, CD5- and CD23-positive lymphoid blasts. We encountered a case of spontaneous splenic rupture in a patient receiving chemotherapy for exacerbating B-cell chronic lymphoid leukemia. In a case of abdominal pain of acute onset in patients with hematological disease, spontaneous splenic rupture should be suspected.