[A Case of Long-Term Survival after Administration of Regorafenib for Stage â £ Colorectal Cancer].

The patient was a 65-year-old man for whom a right hemicolectomy was performed for transverse colon cancer and multiple lymph node metastases. Peritoneal dissemination was observed throughout the abdominal cavity, and curative resection was not possible. Postoperative diagnosis: pT4bN2M1c(P3), Stage Ⅳc, and mutant RAS status. Therapy consisting of mFOLFOX6 plus bevacizumab was started 1 month after surgery, and up to 25 courses were completed. FOLFIRI plus bevacizumab therapy was performed up to 13 courses as the second-line therapy. Regorafenib 80 mg/day was started as the third-line therapy and the dose was gradually increased. It was performed up to 14 courses for about 13 months, without major adverse events, to keep the disease stable or slow its progression. Although up to 5 courses of FTD/TPI plus bevacizumab therapy were delivered as the fourth-line therapy, he died of disease progression. Regorafenib, which has been approved as a salvage line for metastatic colorectal cancer, features many adverse events, and there are few cases in which the approved dose can be administered. In our case, starting at a low dose resulted in fewer adverse events, adequate disease control, and long-term administration.

AUF1, an mRNA decay factor, has a discordant role in Cpeb1 expression.

Cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates polyadenylation and subsequent translation of CPE-containing mRNAs involved in various physiological and pathological phenomena. Although the significance of CPEB1-mediated translational regulation has recently been reported, the detailed regulatory mechanism of Cpeb1 expression remains unclear. To elucidate the post-transcriptional regulatory mechanisms of Cpeb1 expression, we constructed reporter plasmids containing various deletions or mutations in the Cpeb1 mRNA 3' untranslated region (3'UTR). We investigated their expression levels in Neuro2a neuroblastoma cells. We found that Cpeb1 expression is regulated through an AU-rich element in its 3'UTR. Furthermore, the mRNA decay factor AU-rich binding factor 1 (AUF1) regulates Cpeb1 expression, and knockdown of AUF1 upregulates Cpeb1 mRNA expression but results in a decrease in CPEB1 protein levels. These findings indicate that AUF1 has a discordant role in the expression of Cpeb1.

[A Case of Lung Metastases from Rectal Cancer Treated for Quite Long with FOLFIRI plus Ramucirumab as a Late Line of Therapy].

We herein report a case of lung metastases from rectal cancer treated with FOLFIRI plus ramucirumab(Ram)therapy after salvage for a long time. A 44-year-old woman underwent low anterior resection for rectal cancer. Fifteen months after the surgery, mFOLFOX6 plus bevacizumab(BV)therapy was initiated for left obturator lymph node metastases. Although the target lesion shrunk, left lung metastasis was found 36 months after the surgery. Partial resection of the lung metastasis was performed, and carbon-ion radiotherapy for pelvic recurrence was administered. Following these treatments, mFOLFOX6 plus BV therapy was administered again for multiple lung metastases 42 months after the surgery. FOLFIRI plus BV therapy, TAS- 102 plus BV therapy, and regorafenib were then administered because of the disease progression. Although the best supportive care was provided after disease progression, FOLFIRI plus Ram therapy was initiated owing to the patient's wish. Although Grade 3 hematological toxicity was observed, severe digestive symptoms were not noted. Long-term administration(approximately 1 year, 21 courses)of the drugs was possible with withdrawal. The patient died due to disease progression 66 months after recurrence. We experienced a case in which FOLFIRI plus Ram therapy after salvage line could be administered for a quite long time. It has been suggested that anti-VEGF drugs with different targets may improve the prognosis even as a late line of therapy if it is tolerable.

[Efficacy of Negative Pressure Wound Therapy for Post-Operative Wound Dehiscence after Resection of a Metastatic AbdominalWal lTumor from Cecal Cancer during Chemotherapy with Bevacizumab].

A 74-year-old man with recurrence of cecal cancer received systemic chemotherapy(CapeOX plus bevacizumab). After the administration of 9 courses, he reported sudden appearance of bloody bowel discharge. Endoscopic examination could not locate the bleeding point. A CT scan indicated that the small intestine was affected by the recurrence of cancer. Therefore, resection of the small intestine was performed after 6 weeks of drug withdrawal. Although direct closure with fascia incision was performed for the repair of wound dehiscence after surgery, re-dehiscence occurred because of paralytic ileus. Wound lavage and nutritional intervention were performed, followed by negative pressure wound therapy. Excellent wound healing was achieved by this therapeutic approach for 3 months.

Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene­like 1 (Plagl1), which encodes a C2H2 zinc­finger transcription factor, occurs in hypocretin neuron­ablated transgenic mice, suggesting that PLAGL1 is co­expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro­hypocretin transcription is functionally modulated by PLAGL1. Double immunostaining indicated that the majority of hypocretin neurons were positive for PLAGL1 immunoreactivity in the nucleus. Notably, PLAGL1 immunoreactivity in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detected in the nuclei of hypocretin neurons following sleep deprivation. Chromatin immunoprecipitation revealed that endogenous PLAGL1 may bind to a putative PLAGL1­binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription. These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.

[Efficacy of Laparoscopic Surgery for Elderly Patients with Colorectal Cancer Over 80 Years Old].

The efficacy of laparoscopic surgery for elderly patients aged over 80 years who have colorectal cancer was investigated concerning complications. Sixty-five patients over 80 years old who underwent colorectal cancer resection until January 2018 were enrolled. Factors that led to complication were analyzed retrospectively. Thirty-three men and 32 women were included, with a median age of 83 years. Forty-eight cases were located at the colon; and 17, at the rectum. The median operating time was 164 minutes, including 39 cases treated with the laparoscopic approach. Postoperative complications were observed in 28 cases(43.1%), of which 15(23.1%)had a Clavien-Dindo(CD)classification of Grade BⅡ. These cases had significantly prolonged postoperative hospital stay. Complications included 10 cases of incisional surgical site infection(SSI), 9 cases of ileus, 6 cases of melena, 2 cases of urinary infection, 2 cases of urinary disorder, and 1 case of postoperative death. Open surgery was the only significant factor associated with the incidence of CD classification of BⅡ(p=0.0330). Among the complications, the incisional SSI was reduced by laparoscopic surgery(p=0.0050). The number of laparoscopic surgeries reduced the incidence of CD classification BⅡ of complications in elderly patients aged over 80 years who had with colorectal cancer resection. The use of incisional SSI also decreased with the use of laparoscopic surgery. Laparoscopic surgery for colorectal cancer in elderly patients may lead to reduced complication rates.

[A Case of Neuroendocrine Carcinoma of the Ascending Colon That Responded Completely to Chemotherapy].

We report a case of effective treatment comprising mFOLFOX6 plus bevacizumab for neuroendocrine carcinoma of the ascending colon. A 60-year-old woman was admitted for diarrhea and abdominal pain. Colonoscopy showed a Type 2 tumor in the ascending colon. She was diagnosed with neuroendocrine cell carcinoma based on biopsy and immunostaining. CT and MRI showed liver metastasis and lymph node #12a metastasis. Right hemi-colectomy, lymphadenectomy, and partial hepatectomy were performed(T4a, N2, M1b, Stage IV). Neuroendocrine cell carcinoma(small-cell type)was finally diagnosed based on a histological examination because the nuclear fission image was 30(/10HPF)and the Ki-67 index was 42%. Three months after the surgery, multiple lymph node metastases were found using CT and MRI. mFOLFOX6 plus bevacizumab was initiated. After 4 courses of the chemotherapy, the metastases responded completely. A total of 10 courses of chemotherapy were administered. About 2 years and 6 months after the surgery, no recurrence is allowed.

[Analyses of Relapsed Cases after Oxaliplatin-Based Adjuvant Chemotherapy for Colorectal Cancer with Cur A Resection].

INTRODUCTION: There are few reports on the outcome of relapsed cases after curative resection for colorectal cancer(CRC) with adjuvant oxaliplatin-based chemotherapy. Thus, we analyzed such cases. PATIENTS AND METHOD: In total, 48 patients with CRC who received oxaliplatin-based postoperative adjuvant chemotherapy from 2012 were analyzed. The clinical course was examined in 9 cases ofrecurrence. RESULTS: Stages II, III a, and III b(1, 3, and 5 cases, respectively)were judged as recurrence in 9 cases. Metastatic sites were the lungs, local sites, liver, and peritoneum(3, 3, 3, and 1 case[s], respectively). The median time to relapse was 390 days. There were 2 cases ofwild -type RAS and 7 cases ofmutant RAS. Although R0 resection was performed in 1 case, re-relapse was recognized. Another 8 cases involved induced chemotherapy. An oxaliplatin-based regimen was administered as first-line treatment in 4 of8 cases. At present, 5 patients died, and 3 of8 cases could not progress to second-line treatment. The overall survival(OS)after relapse was 475 days, and survival more than 3 years was not observed. CONCLUSION: Recurrent cases after Cur A resection for CRC with oxaliplatin-based adjuvant chemotherapy were examined. Although the 3-year RFS and 5-year OS were relatively good, the prognosis after relapse was quite poor.

[A Case of Stage IV Rectal Cancer Achieving Long-Term Stable Disease Treated with Chemotherapy and Residual Tumor Resection].

We herein report a Stage IV case ofrectal cancer in a patient who achieved stable disease and was treated monthly with fluorouracil(FU)monotherapy plus bevacizumab(Bmab)against relapse after residual tumor resection and withdrawal because ofref usal to continue chemotherapy, even though a marked response was obtained with standard chemotherapy. A 73-year-old woman visited a former hospital in 2014, and was diagnosed with rectal cancer with liver and lung metastases (diagnosed with Rb, T3, M1b[liver, lung]cStage IV). Chemotherapy(mFOLFOX6 plus Bmab)was initiated with a consideration of conversion. After 5 courses, she moved to our hospital. Since she was not aggressive to chemotherapy from the beginning, an imaging examination was performed after 9 courses. The primary lesion and lung metastases had disappeared, and there was only one liver metastasis. Partial hepatic resection was performed to attempt chemotherapy withdrawal following informed consent. Six months after surgery with no therapy, since relapse in the rectum and lungs was confirmed, laparoscopic rectal amputation was performed to control the primary tumor. Chemotherapy containing FU monotherapy plus Bmab was reinitiated after 15 months of withdrawal because liver and lung metastases increased 5 months after rectal amputation. Two months after resuming chemotherapy, the metastatic lesion decreased in size, and the tumor marker level normalized. The same regimen is continued monthly, and the response has been maintained for 17 months(infusions of 5-FU/LV plus Bmab, 18 courses).

Involvement of DHH and GLI1 in adrenocortical autograft regeneration in rats.

Bilateral adrenalectomy forces the patient to undergo glucocorticoid replacement therapy and bear a lifetime risk of adrenal crisis. Adrenal autotransplantation is considered useful to avoid adrenal crisis and glucocorticoid replacement therapy. However, the basic process of regeneration in adrenal autografts is poorly understood. Here, we investigated the essential regeneration factors in rat adrenocortical autografts, with a focus on the factors involved in adrenal development and steroidogenesis, such as Hh signalling. A remarkable renewal in cell proliferation and increase in Cyp11b1, which encodes 11-beta-hydroxylase, occurred in adrenocortical autografts from 2-3 weeks after autotransplantation. Serum corticosterone and adrenocorticotropic hormone levels were almost recovered to sham level at 4 weeks after autotransplantation. The adrenocortical autografts showed increased Dhh expression at 3 weeks after autotransplantation, but not Shh, which is the only Hh family member to have been reported to be expressed in the adrenal gland. Increased Gli1 expression was also found in the regenerated capsule at 3 weeks after autotransplantation. Dhh and Gli1 might function in concert to regenerate adrenocortical autografts. This is the first report to clearly show Dhh expression and its elevation in the adrenal gland.

[Surgery for Lower Intestinal Perforation Due to Peritoneal Dissemination].

INTRODUCTION: we examined the cases in which surgery was performed for the lower intestinal perforation due to peritoneal dissemination in our hospital. SUBJECTS: Four cases of lower intestinal perforation of patients with peritoneal dissemination who underwent emergency operation in our hospital were enrolled. RESULTS: Two males and 2 females patients with median age of 65.5 year old(63-71)were included. The perforated sites were 3 cases of small intestine and 1 case of ascending colon, and the APACHE II score at the visit was 14.5(10-16)points. The surgical procedure was performed in 3 cases of resection of the perforated site and 3 cases of stoma creation. In 2 out of 4 cases, it became difficult to control bacterial peritonitis and died on the 16th postoperative day. One case could discharge hospital and continued BSC, survived 4 months after surgery. CONCLUSION: Although long-term prognosis could not be expected, there were cases in which it was possible to restart the oral intake after surgery or discharge. Surgical treatment might be selected for the lower intestinal perforation due to peritoneal dissemination.

[Multiple Resections for Metastases from Colorectal Cancer].

PURPOSE: We analyzed to clarify an outcome of multiple resections of metastases from colorectal cancer. PATIENTS AND METHOD: Total 7 cases who underwent several resections for metastases from colorectal cancer in Saiseikai Kurihashi Hospital after 2010 were enrolled for analysis. RESULT: Age of patients at the time of the primary site resection was 67(45-78)year-old, including 4males and 3 females. Patients located at cecum/ascending/sigmoid/rectosigmoid/upper rectum were 1/1/2/2/1 respectively. Metachronous metastases were found in 5 patients. There were 1 patient for Stage I , 2 patients for Stage III a and III b each and all Stage III patients received adjuvant chemotherapy. The resected organs were 9 in lung, 8 in liver, 1 case in lymph node, local site and peritoneum and the median resected sites were 3(2-4)lesions. In 17 months median observation periods after latest resection, 5 cases have not been prolapsed including 3 cases with chemotherapy. Two cases were relapsed with unresectble status. One case died for 24 months and one case is under the chemotherapy for 12 months. Five year survival rate was 75% and 2 year prolapse free rate was 66.7%, since the relatively good prognosis was obtained by multiple resections. CONCLUSION: The cases that multiple resections with R0 were able to perform for the metastases were analyzed. Although cases which become finally to be unresectable exist, it is suggested that the relatively good prognosis might be obtained by multiple resections for metastases.

Establishment of a tumor sphere cell line from a metastatic brain neuroendocrine tumor.

Neuroendocrine tumors are rare, and little is known about the existence of cancer stem cells in this disease. Identification of the tumorigenic population will contribute to the development of effective therapies targeting neuroendocrine tumors. Surgically resected brain metastases from a primary neuroendocrine tumor of unknown origin were dissociated and cultured in serum-free neurosphere medium. Stem cell properties, including self-renewal, differentiation potential, and stem cell marker expression, were examined. Tumor formation was evaluated using intracranial xenograft models. The effect of temozolomide was measured in vitro by cell viability assays. We established the neuroendocrine tumor sphere cell line ANI-27S, which displayed stable exponential growth, virtually unlimited expansion in vitro, and expression of stem-cell markers such as CD133, nestin, Sox2, and aldehyde dehydrogenase. FBS-induced differentiation decreased Sox2 and nestin expression. On the basis of real-time PCR, ANI-27S cells expressed the neuroendocrine markers synaptophysin and chromogranin A. Intracranial xenotransplanted brain tumors recapitulated the original patient tumor and temozolomide exhibited cytotoxic effects on tumor sphere cells. For the first time, we demonstrated the presence of a sphere-forming, stem cell-like population in brain metastases from a primary neuroendocrine tumor. We also demonstrated the potential therapeutic effects of temozolomide for this disease.

Hypothalamo­hypophysial system in rats with autotransplantation of the adrenal cortex.

Patients with bilateral pheochromocytoma often require an adrenalectomy. Autotransplantation of the adrenal cortex is an alternative therapy that could potentially be performed instead of receiving glucocorticoid replacement following adrenalectomy. Adrenal cortex autotransplantation aims to avoid the side effects of long­term steroid treatment and adrenal insufficiency. Although the function of the hypothalamo­hypophysial system is critical for patients who have undergone adrenal cortex autotransplantation, the details of that system, with the exception of adrenocorticotropic hormone in the subjects with adrenal autotransplantation, have been overlooked for a long time. To clarify the precise effect of adrenal autotransplantation on the pituitary gland and hypothalamus, the current study examined the gene expression of hormones produced from the hypothalamus and pituitary gland. Bilateral adrenalectomy and adrenal autotransplantation were performed in 8 to 9­week­old male rats. The hypothalamus and pituitary tissues were collected at 4 weeks after surgery. Transcriptional regulation of hypothalamic and pituitary hormones was subsequently examined by reverse transcription­quantitative polymerase chain reaction. Proopiomelanocortin, glycoprotein hormone α polypeptide, and thyroid stimulating hormone ß were significantly elevated in the pituitary gland of autotransplanted rats when compared with sham­operated rats. In addition, there were significant differences in the levels of corticotropin releasing hormone receptor 1 (Crhr1), Crhr2, nuclear receptor subfamily 3 group C member 1 and thyrotropin releasing hormone receptor between the sham­operated rats and autotransplanted rats in the pituitary gland. In the hypothalamus, corticotropin releasing hormone and urocortin 2 mRNA was significantly upregulated in autotransplanted rats compared with sham­operated rats. The authors identified significant alterations in the function of not only the hypothalamus­pituitary­adrenal axis, but also the adenohypophysis thyrotropes in autotransplanted rats. In the future, it will be important to examine other tissues affected by glucocorticoids following adrenal cortex autotransplantation.

[A Case of Hepatectomy for Liver Metastases during Long-Term Chemotherapy after Three Hepatectomies for Liver Metastases from Rectal Cancer].

We report the case of a 78-year-old man with liver metastases from rectal cancer treated with hepatectomy after 14 months of chemotherapy. This was the fourth hepatic recurrence after hepatectomy. Distant metastasis of colorectal cancer can be considered for resection, if it can be an R0 resection; however, there is no consensus regarding the timing and extent of resection. Although a study has shown the efficacy of perioperative chemotherapy for resectable liver metastasis from colorectal cancer, the regimen and duration of chemotherapy has not been established yet. It is important that an adequate treatment should be selected for each case, such as chemotherapy as systemic therapy and surgery as local therapy.

Sox2 promotes survival of satellite glial cells in vitro.

Sox2 is a transcriptional factor expressed in neural stem cells. It is known that Sox2 regulates cell differentiation, proliferation and survival of the neural stem cells. Our previous study showed that Sox2 is expressed in all satellite glial cells of the adult rat dorsal root ganglion. In this study, to examine the role of Sox2 in satellite glial cells, we establish a satellite glial cell-enriched culture system. Our culture method succeeded in harvesting satellite glial cells with the somata of neurons in the dorsal root ganglion. Using this culture system, Sox2 was downregulated by siRNA against Sox2. The knockdown of Sox2 downregulated ErbB2 and ErbB3 mRNA at 2 and 4 days after siRNA treatment. MAPK phosphorylation, downstream of ErbB, was also inhibited by Sox2 knockdown. Because ErbB2 and ErbB3 are receptors that support the survival of glial cells in the peripheral nervous system, apoptotic cells were also counted. TUNEL-positive cells increased at 5 days after siRNA treatment. These results suggest that Sox2 promotes satellite glial cell survival through the MAPK pathway via ErbB receptors.