Haruki Sada

An Analysis of Surgical Treatment for the Spontaneous Rupture of Hepatocellular Carcinoma

Background/Aims: The prognosis of spontaneous rupture of hepatocellular carcinoma (HCC) remains unclear. We investigated the prognosis of patients with ruptured HCC based on the treatments and prognostic factors associated with long-term survival. Methods: The prognoses of 64 consecutive patients treated for ruptured HCC from 1986 to 2013 were analyzed according to their methods of treatment. The prognostic factors of 16 surgical patients were identified, and their overall survival (OS) and recurrence rates were compared to 1,157 surgical patients who underwent surgery for non-ruptured HCC. The surgical outcomes were also compared using a propensity score matching method. Results: Surgery was associated with a better OS. Curative resection was the only independent prognostic factor in surgical patients with ruptured HCC (p = 0.040). Although the OS of surgical patients with non-ruptured HCC was found to be significantly better than that of the patients with ruptured HCC, no significant difference in OS was observed after propensity score matching. Conclusion: A curative resection should be the objective of treatment, assuming the suitability of the patients clinical condition. When the liver function reserve and tumor extension of patients with ruptured and non-ruptured HCC are similar, then their surgical outcomes may not be significantly different.

KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer.

KRAS mutations occur in 30–40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apcflox/flox; LSL-KrasG12D and CDX2P-G22Cre;Apcflox/flox mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription–PCR (qRT–PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT–PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin–nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin–NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC.

Gasdermin C Is Upregulated by Inactivation of Transforming Growth Factor β Receptor Type II in the Presence of Mutated Apc, Promoting Colorectal Cancer Proliferation

Mutations in TGFBR2, a component of the transforming growth factor (TGF)-β signaling pathway, occur in high-frequency microsatellite instability (MSI-H) colorectal cancer (CRC). In mouse models, Tgfbr2 inactivation in the intestinal epithelium accelerates the development of malignant intestinal tumors in combination with disruption of the Wnt-β-catenin pathway. However, no studies have further identified the genes influenced by TGFBR2 inactivation following disruption of the Wnt-β-catenin pathway. We previously described CDX2P-G19Cre;Apcflox/flox mice, which is stochastically null for Apc in the colon epithelium. In this study, we generated CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice, with simultaneous loss of Apc and Tgfbr2. These mice developed tumors, including adenocarcinoma in the proximal colon. We compared gene expression profiles between tumors of the two types of mice using microarray analysis. Our results showed that the expression of the murine homolog of GSDMC was significantly upregulated by 9.25-fold in tumors of CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice compared with those of CDX2P-G19Cre;Apcflox/flox mice. We then investigated the role of GSDMC in regulating CRC tumorigenesis. The silencing of GSDMC led to a significant reduction in the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GSDMC enhanced cell proliferation. These results suggested that GSDMC functioned as an oncogene, promoting cell proliferation in colorectal carcinogenesis. In conclusion, combined inactivation of both Apc and Tgfbr2 in the colon epithelium of a CRC mouse model promoted development of adenocarcinoma in the proximal colon. Moreover, GSDMC was upregulated by TGFBR2 mutation in CRC and promoted tumor cell proliferation in CRC carcinogenesis, suggesting that GSDMC may be a promising therapeutic target.

Avoiding restorative proctocolectomy for colorectal cancer in patients with ulcerative colitis based on preoperative diagnosis involving p53 immunostaining: report of a case.

The standard operation for colitic cancer in ulcerative colitis (UC) is restorative proctocolectomy; however, sporadic colorectal cancer (CRC) can coincidentally arise in patients with UC and the optimal procedure remains controversial. Therefore, it is crucial to preoperatively determine whether the CRC in UC is a sporadic or colitic cancer. We report a case of avoiding proctocolectomy for sporadic CRC in a patient with UC based on preoperative diagnosis involving p53 immunostaining. A 73-year-old man with CRC in UC had undergone sigmoid colectomy with lymphadenectomy because of the submucosal deep invasion pathologically after endoscopic mucosal resection. The cancer was diagnosed sporadic cancer preoperatively not only based on the endoscopic, clinical, and histological patterns but also that the colon epithelium was unlikely to develop dysplasia as the circumference and unaffected UC mucosa did not detect p53 protein overexpression. Recent reports have shown that the immunohistochemical detection of p53 protein overexpression can be useful for a differential diagnosis and as a predictor of dysplasia and colitic cancer. The analysis of p53 mutation status based on immunostaining of p53 protein expression in the unaffected UC mucosa can be useful for the decision regarding a surgical procedure for CRC in patients with UC.

Surgical techniques for advanced transverse colon cancer using the pincer approach of the transverse mesocolon

BackgroundLaparoscopic surgery for colorectal cancer, not only early cancer but also advanced cancer, has become standardized by some randomized controlled studies. However, cases involving advanced transverse colon cancer were excluded from these studies due to the technical difficulty of the surgery. Hence, laparoscopic surgery for advanced transverse colon cancer is still a theme that we need to overcome. To solve these issues, it is necessary to establish a standardized approach and surgical technique.Surgical techniquesThe advantage of our method, which approaches from both sides of the transverse mesocolon, is that it is easier to achieve hemostasis when active bleeding occurs because this approach provides space for ligating and sealing. This allows the surgeon to perform lymphadenectomy around the superior mesenteric artery and vein.ConclusionsWe introduced the usefulness of the “Pincer approach of the transverse mesocolon” to standardize laparoscopic surgery for advanced transverse colon cancer.

A case of ascending colon cancer accompanied with tumor thrombosis in the superior mesenteric vein treated with right hemicolectomy and greater saphenous vein grafting

Highlights • The occurrence of colorectal cancer with tumor thrombosis in the mesenteric vein is very rare.• Complete resection of the primary cancer with tumor thrombosis is essential.• Combined surgery and chemotherapy should be performed to prevent recurrence.

Increased Calcineurin A Expression Is Associated with a Lower Relapse-Free Survival Rate after Colorectal Cancer Surgery

Objective: Increased expression of calcineurin in colorectal cancer (CRC) has been reported. Although the oncogenic function has been suggested, the clinical relevance is still unclear. We herein studied calcineurin expression as a prognostic biomarker in patients receiving curative surgery for stages I-III CRC. Methods: In 121 patients with stages I-III CRC treated at Hiroshima University between 1997 and 2003, calcineurin A expression was examined using immunohistochemistry (IHC) staining of surgical specimens. Specimens were considered positive for calcineurin A if any IHC-stained cells were observed within the carcinomatous area, and clinicopathological characteristics and survival outcomes were compared between IHC-positive and -negative groups. Results: Calcineurin A was preferentially expressed in the cytoplasm of cancer cells, and a median of 8% of the cells (range: 0-80%; interquartile range: 0-22.5%) were stained within the carcinomatous areas. Of 121 cases, 81 were determined as IHC positive while 40 were determined to be negative. Positive expression of calcineurin A, as well UICC-TNM stage, was associated with low relapse-free survival (RFS) rates in multivariate analyses (hazard ratio = 2.92; 95% CI: 1.27-7.92; p = 0.010). Conclusion: Increased calcineurin A expression is associated with lower RFS rates and may have clinical value in predicting recurrence.

Effects of nutritional supplementation with selenium and zinc on natural killer cell activity in hemodialysis patients: a single-arm study

of energy, 1.0 g of protein, 12 types of vitamin and 10 types of mineral including 50 μg of Se and 12 mg of Zn once a day for 3 months. We examined the effect of this formula on the NK cell activity and cardiac function in 18 patients undergoing maintenance HD (age: 73 ± 13 years, HD vintage: 64 ± 89 months, male/female = 10/8). This administration significantly increased the serum Se and Zn levels after 3 months (Table 1). A significant increase was found in the NK cell activities (as assessed by a standard 51 Cr release assay against K562) at an E/T ratio of 10:1 and 20:1, respectively (Table 1). In HD patients, Zn supplementation alone did not restore the immune hypo-responsiveness to a multivalent influenza vaccine [7]. Since both Zn and Se administration improved the NK cell activity in cancer patients [8], concomitant Zn and Se supplementation may enhance the NK cell activity. Se deficiency leads to oxidative stress and inflammation which can cause protein energy wasting [9]. However, the formula did not change the nutritional or inflammatory parameters (data not shown). Long-term Se deficiency can cause cardiac dysfunction. Micronutrient supplementation including 50 μg/day of Se and 15 mg/day of Zn improves left ventricular (LV) dysfunction in chronic heart failure patients [10]. Treatment with Se and Zn administration mitigated LV hypertrophy in Seand Zn-deficient patients with intestinal malabsorption due to bypass surgery [11]. However, no study has so far examined the effect of Se and Zn administration on cardiac dysfunction in dialysis patients. We herein showed, for the first time, that the formula significantly decreased the LV end-diastolic dimension after 3 months of concomitant Zn and Se supplementation (Table 1). This study was not carried out in a randomized and controlled fashion. The number of patients was also quite Editor, Natural killer (NK) cells have a potent cytolytic activity against infected cells. NK cells play a crucial role in the host defense against severe infections [1]. Micronutrient intake, especially selenium (Se) and zinc (Zn), is reported to be associated with the NK cell activity. The plasma Se and Zn levels positively correlate with the NK cell number [2]. Se supplementation increased the expression of the genes associated with NK cell cytotoxicity [3]. Zn supplementation also upregulates the lytic activity of NK cell in the elderly [4]. Both Se and Zn deficiencies are often observed in hemodialysis (HD) patients [5]. We previously found an association between Se deficiency and an impaired NK cell activity [6]. However, whether the oral supplementation of Se and Zn can restore an impaired NK cell activity in HD patients remains unclear. We provided a 125 mL of vitamin–mineral-rich drink (V CRESC: NUTRI Co. Ltd., Mie, Japan) containing 80 kcal