Characterization of cell line with dedifferentiated GIST-like features established from cecal GIST of familial GIST model mice.

Approximately 40 families with multiple gastrointestinal stromal tumors (GISTs) and germline c-kit gene mutations have been reported. Three knock-in mouse models have been generated, and all the models showed a cecal GIST. In the present study, we established a cell line derived from cecal GIST in a familial GIST model mouse with KIT-Asp818Tyr. Since the established cells showed spindle-shaped morphology with atypical nuclei, and since immunohistochemistry revealed that they were positive for α-SMA but negative for KIT, CD34 and desmin, the phenotypes of the cells were reminiscent of dedifferentiated GIST-like ones but not the usual GIST-like ones. Gene expression analysis showed that the cell line, designated as DeGISTL1 cell, did not express c-kit gene apparently, but highly expressed HSP90 families and glutaminase 1. Pathway analysis of the cells revealed that metabolic pathway might promote their survival and growth. Pimitespib, a heat shock protein 90α/ß inhibitor, and Telaglenastat, a selective glutaminase 1 inhibitor, inhibited proliferation of DeGISTL1 cells and the combination of these showed an additive effect. DeGISTL1 cells might be a good model of dedifferentiated GISTs, and combination of Pimitespib and Telaglenastat could be a possible candidate for treatment strategy for them.

CADM1 promotes adhesion to vascular endothelial cells and transendothelial migration in cultured GIST cells.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract. Small intestinal GISTs appear to be associated with poorer prognosis and higher metastasis rate than gastric GISTs of the same size and mitotic index. Recently, we reported that cell adhesion molecule 1 (CADM1) is expressed specifically in most small intestinal GISTs, but not in most gastric GISTs, suggesting that this difference in CADM1 expression between gastric GISTs and small intestinal GISTs might influence the difference in clinical behavior between them. The aim of the present study was to examine whether high CADM1 expression affected proliferation, migration, invasion, adhesion to endothelial cells and transendothelial migration of cultured GIST cells by comparing original GIST-T1 cells with very low CADM1 expression with GIST-T1 cells with high CADM1 expression induced by CADM1 cDNA transfection (GIST-T1-CAD cells). GIST-T1-CAD cells had reduced ability to proliferate, migrate and invade compared with the original GIST-T1 cells, but showed significantly higher ability to adhere to human umbilical vein endothelial cells and migrate through endothelial cell monolayers. Thus, CADM1 may contribute to higher metastasis rates in small intestinal GISTs facilitating tumor cell adhesion to vascular endothelial cell and transendothelial migration of tumor cells. CADM1 might serve as a potential target for inhibition of metastasis in small intestinal GISTs.

MRI Finding of Prostatic Ductal Adenocarcinoma.

Ductal adenocarcinoma is a variant of prostatic adenocarcinoma, originating from the epithelial lining of the primary and secondary ducts of the prostate. We report a 63-year-old male with prostatic ductal adenocarcinoma, presenting as urinary retention and a prostate-specific antigen (PSA) level of 11.71 ng/mL and biopsy-proven prostate cancer (Gleason score 3 + 3). MRI showed 2 hemorrhagic, multilocular cysts projecting into the bladder side from the prostatic inner gland and between the prostate and the right seminal vesicle. The prostate inner gland showed high signal intensity on the T2-weighted image and included tiny hyperintense spots on the fat-suppression T1-weighted image. In the part of the border of the hemorrhagic, multilocular cyst, a solid portion showing slight low intensity on T1-weigthed imaging and markedly restricted diffusion was observed, suggesting prostate cancer. He underwent total prostatectomy, and ductal adenocarcinoma (Gleason score 4 + 4) in the prostate inner gland and multilocular cysts was pathologically diagnosed. After the operation, his PSA level gradually increased, and MRI 8 months after the operation showed a vesical multilocular cyst, suggesting local recurrence. After he underwent radiation therapy and hormonal therapy, PSA level decreased, and no re-recurrence was observed during 8 years. We suggest its inclusion in the differential diagnosis of cases of prostatic ductal adenocarcinoma's multiloculated cystic formation around the prostate and the bladder.

Pimitespib is effective on cecal GIST in a mouse model of familial GISTs with KIT-Asp820Tyr mutation through KIT signaling inhibition.

Three families with multiple gastrointestinal stromal tumors (GISTs) caused by a germline Asp820Tyr mutation at exon 17 of the c-kit gene (KIT-Asp820Tyr) have been reported. We previously generated a knock-in mouse model of the family, and the mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal tumor equivalent to human GIST. In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. In this report, we examined whether a heat shock protein 90 inhibitor, pimitespib (TAS-116), has an inhibitory effect on phosphorylation of KIT-Asp818Tyr and can decrease the cecal tumor volume in the model mice. First, we showed that pimitespib inhibited KIT phosphorylation both dose- and time-dependently in KIT-Asp818Tyr transfected murine Ba/F3 cells. Then, four 1-week courses of pimitespib were orally administered to heterozygous (KIT-Asp818Tyr/+) model mice. Each course consisted of once-daily administration for consecutive 5 days followed by 2 days-off. Cecal tumors were dissected, and tumor volume was histologically analyzed, Ki-67 labeling index was immunohistochemically examined, and apoptotic figures were counted. Compared to the vehicle treated mice, pimitespib administered mice showed statistically significantly smaller cecal tumor volume, lower Ki-67 labeling index, and higher number of apoptotic figures in 10 high power fields (P = 0.0344, P = 0.0019 and P = 0.0269, respectively). Western blotting revealed that activation of KIT signaling molecules was strongly inhibited in the tumor tissues of pimitespib-administered mice compared to control mice. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib.

Differential Expression of CADM1 in Gastrointestinal Stromal Tumors of Different Sites and with Different Gene Abnormalities.

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, differentiating toward the interstitial cell of Cajal (ICC), arises predominantly in the stomach and small intestine. Small intestinal GISTs appear to have worse prognosis than gastric GISTs. In a pilot study of a cDNA expression chip using several GISTs, we found that Cell Adhesion Molecule 1 (CADM1), which could contribute to tumor growth and infiltration, is expressed more strongly in small intestinal GISTs than gastric GISTs. In the present study, we examined CADM1 expression in GISTs of different sites and with different gene abnormalities using a large number of gastric and small intestinal GISTs. First, immunoblotting confirmed significantly higher CADM1 expression in small intestinal GISTs with exon 11 c-kit mutation than gastric GISTs with exon 11 c-kit mutation. Real-time PCR also revealed that small intestinal GISTs with exon 11 c-kit mutation showed significantly higher CADM1 mRNA than gastric GISTs with exon 11 c-kit mutation. Although most small intestinal GISTs showed high CADM1 mRNA expression regardless of gene abnormality types, different CADM1 expression was detected between gastric GISTs with c-kit mutation and those with PDGFRA mutation. Immunohistochemistry showed that many small intestinal GISTs were CADM1-positive but most gastric GISTs CADM1-negative or -indefinite. In the normal gastric and small intestinal walls, immunoreactivity of CADM1 was detected only in nerves, but neither in gastric ICCs nor small intestinal ICCs, indicating that the high CADM1expression in small intestinal GISTs might be acquired during tumorigenesis. Different CADM1 expression between gastric and small intestinal GISTs might be related to different prognoses between them. Further functional experiments are needed to elucidate the role of CADM1 on GIST biology, and there is a possibility that targeting therapy against CADM1 has a preventive effect for tumor spreading in small intestinal GISTs.

CT Findings of Primary Renal Angiosarcoma.

Primary angiosarcomas of the kidney are very rare but highly aggressive tumors showing poor prognosis. We present a case of primary renal angiosarcoma occurring in a 60-year-old man with left flank pain. CT images depicted a huge exophytic mass (14 cm in diameter) in the left kidney, exhibiting central extensive hemorrhage or necrosis without contrast enhancement. The mass showed centripetal peripheral nodular enhancement on dynamic contrast-enhanced CT images. We suggest its inclusion in the differential diagnosis of cases of hemorrhagic renal tumors with prominent vasculature.

Pelvic MRI, FDG-PET/CT, and Somatostatin Receptor Scintigraphy Findings of Treatment-Related Neuroendocrine-Differentiated Prostate Cancer.

Treatment-related neuroendocrine-differentiated prostate cancer (NEPC) is a rare tumor entity that transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. We report a 79-year-old male with treatment-related NEPC, presenting as rectal bleeding after hormonal therapy. MRI showed a 51 × 52 × 65 mm tumor occupying almost the whole prostate gland and invading the seminal vesicle and rectum as moderately heterogeneous hypointensity on T2-weighted image, restricted diffusion on apparent diffusion coefficient map and diffusion-weighted imaging, and heterogeneous enhancement on Gd-enhanced T1-weighted image. FDG-PET/CT showed strong FDG uptake of the prostate tumor, and somatostatin receptor scintigraphy (SRS) showed mild uptake of the prostate tumor. The surgically resected specimen revealed NEPC. If prostate cancer worsens despite conventional therapy, treatment-related NEPC should be considered, and the benefit of imaging examinations including prostate MRI, FDG-PET/CT, and SRS is in localizing lesions with neuroendocrine differentiation.

A case of planar-type GIST of the sigmoid colon showing diverticular structure with perforation.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) generally form well-defined mass lesions. However, some cases of the flatly distributed and muscularis propria-replacing GISTs have been reported so far. We experienced an additional case of planar-type GIST of the sigmoid colon accompanied by a diverticulum with perforation. CASE PRESENTATION: A 68-year-old Japanese male with sudden onset of abdominal pain was clinically diagnosed with gastrointestinal perforation, and an emergency abdominal operation was performed. A diverticulum with rupture was found in the sigmoid colon, but no apparent tumor was observed. Histological examination revealed bland spindle cells flatly proliferating and diffusely replacing the muscularis propria at the diverticular structure. The spindle cells were positive for KIT, DOG1, and CD34. Mutational analysis of the c-kit gene revealed that the lesion had a heterozygous deletion of 2 amino acids at codons 557 and 558 of exon 11. The mutation was not observed in the normal mucosa of the surrounding tissue. CONCLUSION: We diagnosed this case as an unusual planar-type GIST. Some similar cases have been reported in the sigmoid colon and other sites. We discuss the mechanism of development of the planar-type GISTs associated with the diverticulum.

Tiny Obturator Node Metastasis from Prostate Cancer Not Shown by FDG-PET/CT, CT, or MRI Detected by 11C-Choline PET/CT.

We report a 65-year-old male with histopathologically proven prostate cancer and multiple pelvic node metastases using a robotic-assisted radical prostatectomy procedure plus extended pelvic lymph node dissection. Positron emission tomography (PET) scan findings demonstrated a moderate accumulation of 11C-choline in a metastatic left obturator node sized 8 × 8 mm, though only a faint uptake of fluorodeoxyglucose (FDG) was noted. 11C-choline PET/computed tomography (CT) may be useful for the diagnosis of a tiny metastatic lymph node not demonstrated by CT, magnetic resonance imaging, or FDG-PET/CT and to determine the need for an extended pelvic lymph node dissection.