FMS‐like tyrosine kinase 3 (FLT3) amplification in patients with metastatic colorectal cancer

FMS‐like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co‐altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co‐alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non‐FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted.     

Gene amplification of YB‐1 in castration‐resistant prostate cancer in association with aberrant androgen receptor expression

Although Y‐box binding protein‐1 (YB‐1) is known to be overexpressed in prostate cancer, especially castration‐resistant prostate cancer (CRPC), the mechanism of its overexpression remains unclear. We aimed to elucidate the mechanism of YB‐1 overexpression in CRPC. Gene amplification in CRPC cells and tissues was examined by public database analysis, and digital PCR. The significance of YB‐1 amplification for the YB‐1/androgen receptor (AR) axis and prognosis was examined by public database analysis and immunohistochemistry. YB‐1 amplification was mainly observed in CRPC tissues by public database analysis and confirmed in CRPC cells and tissues by digital PCR. Expression of YB‐1 was increased in CRPC tissues compared with treatment‐naïve tissues. Furthermore, YB‐1 and phosphorylated YB‐1 levels were associated with AR and AR V7 expression levels. Finally, YB‐1 amplification was associated with poor outcomes in CRPC. Taken together, the present findings suggest that YB‐1 amplification contributes to progression to CRPC through regulation of AR and AR V7 expressions, and that YB‐1 is a promising therapeutic target in CRPC.     

Short- and long-term oncological outcomes of totally laparoscopic gastrectomy versus laparoscopy-assisted gastrectomy for clinical stage I gastric cancer

Gastric Cancer - Totally laparoscopic gastrectomy (TLG), which involves a complete intracorporeal gastric transection and the creation of an anastomosis, has been gradually adopted. However, a...     

Spatiotemporal metabolic dynamics of the photosensitizer talaporfin sodium in carcinoma and sarcoma

Photodynamic therapy (PDT) using the photosensitizer talaporfin sodium (talaporfin) is a new mode of treatment for cancer. However, the metabolic mechanism of talaporfin has not been clarified. Thus, we investigated the uptake, transportation, and elimination mechanisms of talaporfin in carcinoma and sarcoma. The results showed that talaporfin co‐localized in early endosomes and lysosomes. Talaporfin uptake was via clathrin‐ and caveolae‐dependent endocytosis and a high amount of intracellular ATP was essential. Inhibition of lysosomal enzymes maintained intracellular talaporfin levels. Inhibition of K‐Ras signaling reduced talaporfin uptake in carcinoma and sarcoma cell lines. Talaporfin was taken up by clathrin‐ and caveolae‐dependent endocytosis, translocated from early endosomes to lysosomes, and finally degraded by lysosomes. We also demonstrated that ATP is essential for the uptake of talaporfin and that activation of K‐Ras is involved as a regulatory mechanism. These results provide new insights into the metabolism of talaporfin in cancer cells for the enhancement of PDT for carcinoma and sarcoma.     

CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M–positive lung cancer after osimertinib

International Journal of Clinical Oncology - We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance...     

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with febrile urinary tract infection

Common pathogens of clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) are viruses, such as influenza virus. However, bacteria are rare pathogens for MERS. We report the first patient with MERS associated with febrile urinary tract infection. A 16-year-old lupus patient was admitted to our hospital. She had fever, headache, vomiting, and right back pain. Urinary analysis showed leukocyturia, and urinary culture identified Klebsiella pneumoniae. Cerebrospinal fluid examination and brain single-photon emission computed tomography showed no abnormalities. Therefore, she was diagnosed with febrile urinary tract infection. For further examinations, 99mTc-dimercaptosuccinic acid renal scintigraphy showed right cortical defects, and a voiding cystourethrogram demonstrated right vesicoureteral reflux (grade II). Therefore, she was diagnosed with right pyelonephritis. Although treatment with antibiotics administered intravenously improved the fever, laboratory findings, and right back pain, she had prolonged headaches, nausea, and vomiting. T2-weighted, diffusion-weighted, and fluid attenuated inversion recovery images in brain magnetic resonance imaging showed high intensity lesions in the splenium of the corpus callosum, which completely disappeared 1 week later. These results were compatible with MERS. To the best of our knowledge, our patient is the first patient who showed clinical features of MERS associated with febrile urinary tract infection. Conclusion: In patients with pyelonephritis and an atypical clinical course, such as prolonged headache, nausea, vomiting, and neurological disorders, the possibility of MERS should be considered.     

Histological features of primary tumors after induction or high-dose chemotherapy in high-risk neuroblastoma

Purpose

In the recent years in Japan, an increasing number of patients with neuroblastoma (NB) are being treated by the “delayed local treatment (DL)” policy, undergoing surgery after the completion of high-dose chemotherapy with hematopoietic stem cell rescue (HDC). We reviewed the histopathological findings of second-look operations, including those of patients treated with DL.

Patients

From 1998 to 2013, 26 patients with high-risk NB underwent radical operation following chemotherapy. Surgery was performed after induction chemotherapy in 17 cases (standard; STD), whereas 9 cases completed induction chemotherapy and HDC before undergoing tumor resection (DL). The amount of necrosis and the degree of differentiation within the post-treatment tumor were assessed.

Results

Eighty-eight percent of the tumors showed necrosis in more than 1/3 of the specimen. Two DL cases showed complete disappearance of viable tumor cells. Amount of necrosis did not affect the prognosis of the patient. Tumors with immature, poorly differentiated phenotypes showed an extremely aggressive thereafter. Though not statistically proven, ¹²³I-MIBG (metaiodobenzylguanidine) uptake may be correlated with the amount of viable cells remaining within the tumor, but not with the degree of differentiation.

Conclusions

Our results support the previous reports advocating that tumors that sustain unfavorable histology after chemotherapy behave aggressively thereafter.     

Histogenesis of microscopic adenoma and hyperplastic (metaplastic) gland in nonpolyposis coli

Histogenesis of microscopic adenoma in nonpolypoid colons (those not included in the special disease group of familial polyposis coli) was investigated using complete serial sections with the following results: Adenoma arises from basal cells in the deep layer of the mucosa; and two types of basal cells found were 1) those which had already undergone changes to adenoma and 2) those which are in their transitional stage to adenomas. Early-phase growth of adenoma is brought about by branching. Individual hyperplastic (metaplastic) glands constituting so-called hyperplastic (metaplastic) polyps are considered to be only an expression of one variant in the growing process of adenomas and the glands showing these changes most characteristically have a serrated pattern. Based on these findings, the histogenesis of adenoma in nonpolypoid colons is shown schematically.     

Questionnaire-based analysis of mefloquine chemoprophylaxis for malaria in a Japanese population

Although mefloquine is the only drug licensed for malaria chemoprophylaxis in Japan, there have been few reports describing the effects of and adverse events in the prophylactic usage of mefloquine in a Japanese population. We therefore performed a questionnaire-based study in 21 travelers who were prescribed mefloquine for malaria chemoprophylaxis between October 2001 and December 2003. The study revealed that only 8 out of 21 (38.1%) of the travelers could complete the prophylaxis schedules. Another 8 travelers (38.1%) with incomplete adherence stated that they did not take mefloquine because of either actually experienced or anticipated adverse events. Twelve of the 16 travelers (75.0%) who took mefloquine complained of at least one adverse event probably related to mefloquine. As an overall impression about mefloquine chemoprophylaxis, 14 of the 21 travelers stated that they would take mefloquine again for the next travel to malaria-endemic areas, although 5 of them were concerned about adverse events. These results suggest that, although mefloquine is an indispensable drug for malaria prevention, other effective and well-tolerated chemoprophylactic antimalarials should be available for Japanese travelers who do not tolerate mefloquine.