Publications by authors named "Kiyonori Tanoue"

28 Publications

  • Page 1 of 1

Implications of PD-1, Tim-3, and TIGIT Expression for Cancer Immunity and Pancreatic Cancer Prognosis.

Anticancer Res 2022 Jul;42(7):3373-3380

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background/aim: The development and application of cancer immunotherapy to pancreatic cancer has not progressed because its efficacy has not been proven in clinical trials. In this study, we aimed to explore potential targets of immune checkpoint inhibitor therapy for pancreatic cancer treatment.

Materials And Methods: We collected resected specimens from 40 patients with pancreatic cancer who underwent resection at our Institution without any preoperative treatment. We evaluated the expression of molecules in the programmed death receptor-1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3)/Galectin-9, and CD155/T cell immunoreceptor with Ig and ITIM domains (TIGIT) pathways using immunohistochemical staining. The correlation between the expression pattern of these molecules and patient prognosis were assessed using Kaplan-Meier analysis.

Results: An increased number of CD8 T cells in pancreatic cancer tissue was significantly associated with a better patient prognosis. Additionally, patients with a higher ratio of PD-1 expression to CD8 T cells had a worse prognosis. We observed no correlation between the Tim-3/Galectin-9 and CD155/TIGIT pathways and patient prognosis.

Conclusion: Modifications in the immune environment to increase T cell infiltration into tumors could result in the PD-1 pathway becoming a potential target to treat pancreatic cancer using immune checkpoint inhibition.
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http://dx.doi.org/10.21873/anticanres.15824DOI Listing
July 2022

[Stenotic ischemic enteritis secondary to intraperitoneal band infiltration: a case report].

Nihon Shokakibyo Gakkai Zasshi 2022 ;119(6):566-572

Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences.

A 55-year-old man presented with vomiting and upper abdominal pain. Two months later, computed tomography revealed jejunal wall thickening and contrast enhancement. Double-balloon endoscopy revealed severe jejunal stenosis and mucosal prolapse. The patient was diagnosed with stenotic ischemic small bowel inflammation and underwent partial small bowel resection. Clinicians should consider intraperitoneal band formation in the differential diagnosis of patients without a history of abdominal surgery or trauma. Surgical resection should be considered to prevent strangulation ileus.
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http://dx.doi.org/10.11405/nisshoshi.119.566DOI Listing
June 2022

Curative resection after chemotherapy and chemoradiotherapy for postoperative recurrence of pancreatic tail cancer in the abdominal wall: a case report.

Surg Case Rep 2022 May 19;8(1):101. Epub 2022 May 19.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: Locoregional recurrence and metastasis to the liver, peritoneum, and lung are the most common recurrent patterns of pancreatic ductal adenocarcinoma (PDAC) after radical resection. Recurrence in the abdominal wall is extremely rare. Herein, we report our experience with a patient who had recurrent PDAC in the abdominal wall with long-term survival by means of multidisciplinary therapy.

Case Presentation: A 76-year-old Japanese woman was diagnosed with resectable pancreatic tail cancer. She underwent distal pancreatectomy with regional lymphadenectomy after two cycles of gemcitabine plus S-1 as neoadjuvant therapy. She also received eight cycles of S-1 as adjuvant chemotherapy. Approximately 14 months after the initial surgery, imaging examinations identified a mass suggesting recurrence in the abdominal wall at the middle wound that involved the transverse colon. After two cycles of gemcitabine plus nab-paclitaxel, chemoradiotherapy (S-1 plus 45 Gy) and seven cycles of modified FOLFIRINOX (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin) were administered. The patient did not develop any new recurrent lesions during chemotherapy and chemoradiotherapy. Therefore, the recurrent lesion in the abdominal wall and the involved transverse colon were resected. We confirmed the lack of peritoneal dissemination during surgery. Pathological examination revealed that the resected lesion was metastasis of primary PDAC, and the surgical margin was 1 mm. However, re-recurrence localized in the abdominal wall was detected 9 months later. The re-recurrent lesion was diagnosed as local recurrence of the first recurrent lesion. We performed a second resection of the abdominal wall using a femoral myocutaneous flap to achieve sufficient surgical margin. The pathological findings of the resected specimen were the same as those of the previous specimens, and the resection margin was negative. The patient's postoperative course was uneventful. Seven years after the initial surgery and 3 years and 7 months after the third surgery, the patient is alive with no signs of recurrence.

Conclusions: Long-term survival could be achieved by radical resection with sufficient surgical margins for recurrence of PDAC in the abdominal wall if new other recurrent lesions, including peritoneal dissemination, are prevented through chemotherapy.
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http://dx.doi.org/10.1186/s40792-022-01452-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117584PMC
May 2022

Multidisciplinary treatment of advanced or recurrent solid pseudopapillary neoplasm of the pancreas: three case reports.

Surg Case Rep 2022 Jan 10;8(1). Epub 2022 Jan 10.

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that predominantly affects young females. Prognosis is excellent; however, 10-15% of patients show metastasis at the time of surgery or develop tumor recurrence after pancreatectomy.

Case Presentation: We reviewed the clinical course of three patients with advanced or recurrent SPN and subsequently underwent multidisciplinary treatment at our institution between 2002 and 2019. The primary tumor was resected in all three patients, and metastases were also resected if indicated. Intensive combined therapy, including re-resection, chemotherapy, ablation, arterial chemoembolization, and radiation therapy, allowed all patients to survive for a long time. The literature review showed that resection seems to be more effective than other treatments for metastatic SPN.

Conclusions: Multidisciplinary treatment, including resection, may improve the prognosis of patients with SPN with recurrence or metastasis.
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http://dx.doi.org/10.1186/s40792-022-01358-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743312PMC
January 2022

Postoperative recurrence with right cervical lymph node metastasis in hepatocellular carcinoma: a case report.

Surg Case Rep 2021 Dec 17;7(1):260. Epub 2021 Dec 17.

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: Hepatocellular carcinoma (HCC) patients with metastases to the cervical lymph nodes are extremely rare, and its clinical course is characterized by rapidly progressive disease. Hence, there have been no reports of metastatic cervical lymph node recurrence indicated after a long postoperative surveillance period.

Case Presentation: The patient was a 63-year-old male who underwent right hepatectomy for HCC of the right upper lobe. Three years after resection, metastatic lymph node recurrence was detected in the subdiaphragm, superior mediastinum, and right cervical lymph nodes. The patient underwent excisional biopsy of the cervical lymph node, followed by molecular-targeted therapy and radiation therapy. Lenvatinib reduced the size of all metastatic lymph nodes and the patient survived for a relatively long period of 43 months after the recurrence was detected.

Conclusions: After resection of HCC in the right upper lobe, there is the possibility of metastatic lymph node recurrence in unusual sites, including the cervical region, and lenvatinib may be effective in those recurrences.
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http://dx.doi.org/10.1186/s40792-021-01352-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677867PMC
December 2021

Clinical Utility and Limitation of Diagnostic Ability for Different Degrees of Dysplasia of Intraductal Papillary Mucinous Neoplasms of the Pancreas Using F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography.

Cancers (Basel) 2021 Sep 15;13(18). Epub 2021 Sep 15.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City 890-8520, Japan.

The diagnostic value of F-fluorodeoxyglucose (FDG) uptake in the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas remains unclear. This study aimed to assess the role of FDG uptake in the diagnosis of different degrees of dysplasia of IPMNs. We retrospectively analyzed the following three points in 84 patients with IPMNs: (1) risk factors to predict high-grade dysplasia (HGD) and invasive carcinoma (INV); (2) the relationship between FDG uptake and glucose transporter 1 (GLUT-1) expression; and (3) the relationship between FDG uptake and the presence of mural nodules. The histopathological diagnosis was low-grade dysplasia (LGD) in 43 patients, HGD in 16, and INV in 25. The maximum standardized uptake value (SUV-max) was significantly higher in INV than in LGD/HGD ( < 0.0001, = 0.0136). The sensitivity and specificity to discriminate INV from LGD/HGD were 80.0% and 86.2%, respectively, using the receiver operator characteristic curve, when the optimal cutoff score of SUV-max was set at 4.03. Those values were not different between HGD and LGD. More than half of HGD patients had low GLUT-1 expression. Taken together, FDG-PET/CT is useful in distinguishing between non-invasive and invasive IPMN. Our results offer critical information that may determine surgical treatment strategies.
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http://dx.doi.org/10.3390/cancers13184633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465733PMC
September 2021

Molecular Pathogenesis and Regulation of the -Family: Involvement of and in Intra-Hepatic Cholangiocarcinoma.

Cancers (Basel) 2021 Jun 4;13(11). Epub 2021 Jun 4.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.

The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the -family members (, and ) are key tumor-suppressive microRNAs that control many oncogenic genes/pathways in several cancers. In this study, we searched for therapeutic targets for ICC using the -family as a starting point. Our functional studies of cell proliferation, migration and invasion confirmed that the -family act as tumor-suppressors in ICC cells. Moreover, in silico analysis revealed that "focal adhesion", "ECM-receptor", "endocytosis", "PI3K-Akt signaling" and "Hippo signaling" were involved in oncogenic pathways in ICC cells. Our analysis focused on the genes for integrin-α6 () and integrin-β1 (), which are involved in multiple pathways. Overexpression of and enhanced malignant transformation of ICC cells. Both and were directly regulated by the -family in ICC cells. Interestingly, expression of / was positively controlled by the transcription factor SP1, and was negatively controlled by the -family. Downregulation of the -family enhanced -mediated / expression in ICC cells. MicroRNA-based exploration is an attractive strategy for identifying therapeutic targets for ICC.
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http://dx.doi.org/10.3390/cancers13112804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200054PMC
June 2021

Clinical Benefits of Conversion Surgery for Unresectable Pancreatic Ductal Adenocarcinoma: A Single-Institution, Retrospective Analysis.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Kagoshima 890-8520, Japan.

Background: Unresectable pancreatic ductal adenocarcinoma (UR-PDAC) has a poor prognosis. Conversion surgery is considered a promising strategy for improving the prognosis of UR-PDAC. This study aimed to investigate the clinical benefits of conversion surgery in patients with UR-PDAC.

Methods: We retrospectively evaluated patients with PDAC who were referred to our department for possible surgical resection between January 2006 and December 2019. Conversion surgery was performed only in patients with UR-PDAC who could expect R0 resection. We analyzed the prognostic factors for overall survival among patients who underwent conversion surgery.

Results: Overall, 638 patients with advanced pancreatic cancer were enrolled in this study. According to resectability, resectable cancer (R) was present in 180 patients, borderline resectable cancer (BR) was present in 60 patients, unresectable locally advanced cancer (UR-LA) was present in 252 patients, and unresectable cancer with distant metastasis (UR-M) was present in 146 patients. Conversion surgery was performed in 20 of the 398 UR cases (5.1%). The median period between the initial therapy and conversion surgery was 15.5 months. According to the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation, the treatment response was CR in one patient, PR in 13, SD in five, and PD in one. Downstaging was pathologically determined in all cases. According to the Evans grading system, grade I was observed in four patients (20%), grade IIb was observed in seven (35%), III was observed in seven (35%), and IV was observed in two (10%). We compared the overall survival period from initial treatment among patients undergoing conversion surgery; the median overall survival durations in the conversion surgery, R, BR, UR-LA, and UR-M groups were 73.7, 32.7, 22.7, 15.7, and 8.8 months, respectively. Multivariate analysis revealed that the presence or absence of chemoradiotherapy (CRT) and the RECIST partial response (PR)/complete response (CR) for the main tumor were statistically significant prognostic factors for overall survival among patients undergoing conversion surgery ( = 0.004 and 0.03, respectively).

Conclusion: In UR-PDAC, it is important to perform multidisciplinary treatment, including CRT with conversion surgery.
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http://dx.doi.org/10.3390/cancers13051057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958855PMC
March 2021

Locally advanced cholangiolocellular carcinoma successfully treated with curative resection after downsizing chemotherapy: a case report.

Surg Case Rep 2021 Jan 26;7(1):34. Epub 2021 Jan 26.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: Cholangiolocellular carcinoma (CoCC) is an extremely rare disease comprising less than 1% of all primary malignant liver tumors. No effective treatment other than resection has been established. Herein, we report a case of locally advanced CoCC diagnosed as unresectable, which was successfully treated with curative resection after downsizing chemotherapy.

Case Presentation: A 59-year-old Japanese woman with chronic hepatitis B was diagnosed with locally advanced intrahepatic cholangiocellular carcinoma. As it was difficult to perform R0 resection in the local hospital, chemotherapy combined with gemcitabine plus cisplatin was administered every 3 weeks. After a total of 10 courses of chemotherapy over 10 months the tumor was shown to be reduced in size by computed tomography imaging, and she was referred to our department for surgical resection. The effect of chemotherapy was classified as a "partial response" in the response evaluation criteria of solid tumors. After adding one course of chemotherapy, an extended left hepatectomy with resection of the caudate lobe was performed. R0 resection was achieved. Based on the pathological findings, the final diagnosis of CoCC was determined and eight courses of S-1 adjuvant chemotherapy were administered. At 14 months after the operation, the patient was alive without tumor recurrence.

Conclusions: Downsizing chemotherapy with gemcitabine and cisplatin may be an effective treatment strategy in locally advanced CoCC. Further evidence is required to establish an optimal strategy for the treatment of locally advanced CoCC.
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http://dx.doi.org/10.1186/s40792-021-01120-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838061PMC
January 2021

Usefulness of F-fluorodeoxyglucose-positron emission tomography/computed tomography in primary cystadenocarcinoma of the mesentery: a case report.

Surg Case Rep 2020 Dec 4;6(1):306. Epub 2020 Dec 4.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: Mesenteric cysts have various histological forms, including mesenteric cystadenomas and borderline cystic neoplasms. Primary cystadenocarcinoma of the mesentery is extremely rare; therefore, the clinical and radiological features of this tumor have not been fully elucidated.

Case Presentation: A 50-year-old Japanese woman had a complaint of a left-sided abdominal distention. Enhanced computed tomography and magnetic resonance imaging revealed a unilocular cystic lesion measuring approximately 10 cm located in the left side of the abdomen. F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) revealed mottled mild FDG uptake in the cyst wall and intense FDG uptake in several mural nodules. The cystic mass with the descending colon was completely removed. Pathological examination of the specimens revealed various histologic patterns of adenocarcinoma, including mucin production in the mural nodules. We eventually diagnosed a primary cystadenocarcinoma arising from the mesentery of the descending colon.

Conclusions: Malignancy should be suspected in mesenteric or retroperitoneal cystic tumors with high FDG uptake, and complete resection should be performed with adequate margins.
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http://dx.doi.org/10.1186/s40792-020-01079-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718357PMC
December 2020

The 1-year outcomes after pancreaticogastrostomy using vertical versus horizontal mattress suturing for gastric wrapping.

Surg Today 2021 Apr 23;51(4):511-519. Epub 2020 Sep 23.

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.

Purpose: To investigate the differences in nutritional status 1 year after pancreaticogastrostomy (PG) using vertical suturing (VS) vs. twin square horizontal mattress (HMS) suturing in patients undergoing pancreaticoduodenectomy (PD).

Methods: The subjects of this study were 134 patients who underwent PD, followed by PG, which was closed by VS in 52 and by HMS in 82. We evaluated the peri- and postoperative factors, nutritional parameters, diameter of the remnant main pancreatic duct, and glucose intolerance 1 year postoperatively.

Results: Forty-five (87%) patients from the VS group and 75 (91%) patients from the HMS group survived for more than 1 year. The incidences of intraabdominal abscess and pancreatic fistula were significantly lower in the HMS group than in the VS group (19.2% vs. 6.6% and19.2% vs. 2.6%, respectively). There were no significant changes in the total protein, serum albumin, and HbA1c levels 1 year postoperatively. The postoperative expansion ratio of the main pancreatic duct diameter was significantly smaller in the HMS group than in the VS group. The strongest risk factor for body weight loss 1 year postoperatively was a non-soft pancreas texture.

Conclusion: HMS was superior to VS for preventing early postoperative complications and did not affect pancreatic function.
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http://dx.doi.org/10.1007/s00595-020-02134-zDOI Listing
April 2021

Retroperitoneal schwannoma sandwiched between abdominal aorta and inferior vena cava. A case report.

Int J Surg Case Rep 2020 24;73:112-115. Epub 2020 Jun 24.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan.

Introduction: Schwannomas are tumors that originate from the Schwann cells present in the nerve sheath of peripheral nerves. They are commonly seen in cephalocervical areas. Schwannomas in the abdominal cavity are rare. Here, we discuss a case of retroperitoneal schwannoma lying dorsal to pancreas with critical relations to surrounding vessels.

Presentation Of Case: A 74 years old asymptomatic male was found with elevated amylase level on his routine blood examination. MR imaging revealed retroperitoneal mass of size 21*18*24 mm. EUS-FNA confirmed retroperitoneal schwannoma. The patient had co-morbid renal disease and was on hemodialysis. During the latest follow up, the tumor was 41*37*41 mm in size located dorsal to the confluence of right renal vein and inferior vena cava. The tumor was in contact with inferior vena cava, horizontal part of duodenum, right renal artery, right kidney, and adrenal gland. The patient underwent laparotomy and the tumor was extract with intact capsule. There were no post-operative complications.

Discussion: Pre-operative diagnosis in retroperitoneal schwannomas is challenging because imaging features are usually non-specific, and biopsy is the only diagnostic technique. EUS-FNA, which has low diagnostic accuracy, is useful in pre-operative diagnosis of small tumors devoid of intra-tumoral degeneration.

Conclusion: Retroperitoneal schwannoma is a rare entity. Preoperative diagnosis and curative resection are technically difficult. Care should be given during preoperative investigations and surgical resection of the tumor. EUS-FNA can be a useful diagnostic tool.
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http://dx.doi.org/10.1016/j.ijscr.2020.06.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363624PMC
June 2020

Anatomic Indications for Using Actuator-driven Pulsed Water Jet for Hepatectomy.

Surg Laparosc Endosc Percutan Tech 2020 Oct;30(5):e33-e38

Department of Digestive Surgery, Breast, and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan.

Background: The clamp crushing method and the use of the Cavitron ultrasonic surgical aspirator (CUSA) are widely accepted techniques for hepatic parenchymal transection. The actuator-driven pulsed water jet (ADPJ) with high tissue selectivity is a new technology that was shown as a safe transection tool in preclinical models, although not much is known about its safety criteria in patients. Therefore, its strongest advantage, the best indications for its use, and its performance in comparison with other transection methods remain to be clarified. In this report, we present several representative cases to help answer these questions.

Methods: We started using the ADPJ in December 2017, only in cases where the tumor was very close to major vessels or attached to them, along a considerable length, to preserve vessels and prevent postoperative liver failure. All the cases underwent highly demanding procedures. We avoided using this device in cases such as liver cirrhosis, where the hepatic parenchyma was very hard.

Results: Six cases fulfilled our limited indications for using ADPJ. The median age and number of tumors were 55 years (10 to 69 y) and 2.5 years (1 to 4 y), respectively. The mean tumor size was 7.8 cm (2.8 to 21 cm), the minimum distance between the tumor and major vessels to be preserved was 0 mm (0 to 4 mm), and the contact length of the tumor and major vessels was 26 mm (19 to 40 mm). Regarding the surgical outcome, the median operation time and blood loss were 559 minutes (508 to 919 min) and 620 mL (230 to 860 mL), respectively. We achieved a negative surgical margin (R0 resection) in all cases.

Conclusions: Using ADPJ, we could perform R0 hepatectomy in all cases, which preoperatively were considered to have a high chance of being margin positive. We consider the best indication for using ADPJ is when the tumor and vessels to be preserved are attached or very close over a long distance.
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http://dx.doi.org/10.1097/SLE.0000000000000819DOI Listing
October 2020

[Single Liver Metastasis of Breast Cancer Mimicking Intrahepatic Cholangiocarcinoma 13 Years after the Primary Surgery-A Case Report].

Gan To Kagaku Ryoho 2020 Jan;47(1):129-131

Dept. of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences.

A 78-year-old woman underwent left total mastectomy for breast cancer at 65 years of age.Thirteen years after the primary surgery, CT showed a single 46mm tumor located in liver segment 4.The tumor was difficult to distinguish between cholangiocellular carcinoma and liver metastasis of the breast cancer.We did not perform biopsy, considering dissemination, and performed left hemihepatectomy and left caudate lobectomy.Pathological findings revealed liver metastasis of breast cancer.Hepatic resection is a useful option in cases of single liver metastasis from breast cancer that are difficult to distinguish from cholangiocellular carcinoma.
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January 2020

Clinical prospects for laparoscopic stoma closure of a temporary loop ileostomy: Initial experience and report.

Asian J Endosc Surg 2020 Oct 17;13(4):618-621. Epub 2020 Feb 17.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan.

Introduction: In closure of a stoma, the small working space and adhesions hinder a precise surgical procedure, compared with conventional approaches to digestive surgery. The aim of this prospective study was to introduce a new technique of laparoscopic stoma closure (LASC).

Materials And Surgical Techniques: After starting with three trocars, it is a priority to dissect around the arising ileum; a linear stapler is precisely inserted in both orifices of the loop stoma and applied two times, extracorporeally. Ultimately, both the oral and anal sides of the loop ileum are cut and closed using a linear cutter stapler in a delta-shaped manner just under the abdominal wall, intracorporeally. Eventually, the arising stoma is removed using an intra-abdominal and cutaneous approach.

Discussion: LASC for patients with a temporary loop ileostomy is safe and feasible. More data and experience will be required to verify the benefits of this new technique.
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http://dx.doi.org/10.1111/ases.12790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687255PMC
October 2020

Lung recurrence and its therapeutic strategy in patients with pancreatic cancer.

Pancreatology 2020 Jan 26;20(1):89-94. Epub 2019 Nov 26.

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University, 8-35-1, Sakuragaoka Kagoshima, 890-8520, Japan.

Background: /Objectives: The lung is a major metastatic site of pancreatic cancer (PC). We aimed to assess the features and prognosis of patients with PC according to the recurrence pattern and the effect of resection of recurrent lung lesion.

Methods: We enrolled 168 PC patients who had undergone macroscopically curative resection. All resected lung tumors were evaluated immunohistochemically for expressions of thyroid transcription factor-1 (TTF-1) and napsin A.

Results: The most common site of first recurrence was the liver and local site, followed by the lung, peritoneum, and lymph node. Lung recurrence was observed significantly later than was liver recurrence. The median survival time (MST) after recurrence in patients with first recurrence in the lung was significantly longer than MST in patients with first recurrence in the liver (15.2 months vs 5.2 months, p = 0.039). Seven patients with lung recurrence underwent resection of the recurrent lesion. Surgical resection of single metastasis limited to the lung showed favorable overall survival after recurrence (MST = 36.5 months). Patients with single metastasis limited to the lung showed significantly lower value of FDG-PET SUV of the primary pancreatic tumor.

Conclusions: Patients with first recurrence in the lung showed better prognosis than did patients with first recurrence in the liver. Single metastasis limited to the lung could benefit from surgical resection and was significantly associated with lower FDG-PET SUV of the primary pancreatic tumor.
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http://dx.doi.org/10.1016/j.pan.2019.11.015DOI Listing
January 2020

Gene Regulation by Antitumor in Pancreatic Ductal Adenocarcinoma: The Clinical Significance of Direct RACGAP1 Regulation.

Cancers (Basel) 2019 Mar 7;11(3). Epub 2019 Mar 7.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890-8580, Japan.

Previously, we established a microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) tissues using RNA sequencing and found significantly reduced expression of . Here, we aimed to investigate the functional significance of and to identify target genes involved in PDAC pathogenesis. Cancer cell migration and invasion were significantly inhibited by ectopic expression of in PDAC cells. Comprehensive gene expression analyses and database searches revealed 25 putative targets regulated by in PDAC cells. Among these target genes, high expression levels of , , , , , and were significant predictors of a poor prognosis of patients with PDAC. In this study, we focused on (Rac guanosine triphosphatase-activating protein 1) because its expression was most significantly predictive of PDAC pathogenesis (overall survival rate: = 0.0000548; disease-free survival rate: = 0.0014). Overexpression of was detected in PDAC clinical specimens, and its expression enhanced the migration and invasion of PDAC cells. Moreover, downstream genes affected by (e.g., , , , and ) are involved in PDAC pathogenesis. Our strategy to identify antitumor miRNAs and their target genes will help elucidate the molecular pathogenesis of PDAC.
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http://dx.doi.org/10.3390/cancers11030327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468488PMC
March 2019

Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8.

J Hum Genet 2019 Jun 11;64(6):521-534. Epub 2019 Mar 11.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Our ongoing analyses identifying dysregulated microRNAs (miRNAs) and their controlled target RNAs have shed light on novel oncogenic pathways in pancreatic ductal adenocarcinoma (PDAC). The PDAC miRNA signature obtained by RNA sequencing showed that both strands of pre-miR-130b (miR-130b-5p, the passenger strand and miR-130b-3p, the guide strand) were significantly downregulated in cancer tissues. Our functional assays revealed that miR-130b-5p significantly blocked the malignant abilities of PDAC cell lines (PANC-1 and SW1990), e.g., cancer cell proliferation, migration, and invasion. A total of 103 genes were identified as possible oncogenic targets by miR-130b-5p regulation in PDAC cells based on genome-wide gene expression analysis and in silico database search. Among the possible targets, high expression of 9 genes (EPS8, ZWINT, SMC4, LDHA, GJB2, ZCCHC24, TOP2A, ANLN, and ADCY3) predicted a significantly poorer prognosis of PDAC patients (5-year overall survival, p < 0.001). Furthermore, we focused on EPS8 because its expression had the greatest impact on patient prognosis (overall survival, p < 0.0001). Overexpression of EPS8 was detected in PDAC clinical specimens. Knockdown assays with siEPS8 showed that its overexpression enhanced cancer cell proliferation, migration, and invasion. Analysis of downstream RNA networks regulated by EPS8 indicated that MET, HMGA2, FERMT1, RARRES3, PTK2, MAD2L1, and FLI1 were closely involved in PDAC pathogenesis. Genes regulated by antitumor miR-130b-5p were closely involved in PDAC molecular pathogenesis. Our approach, discovery of antitumor miRNAs and their target RNAs, will contribute to exploring the causes of this malignant disease.
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http://dx.doi.org/10.1038/s10038-019-0584-6DOI Listing
June 2019

Three-stage laparoscopic surgery in a morbidly obese patient with Hinchey III diverticulitis: a case report.

Surg Case Rep 2019 Feb 15;5(1):24. Epub 2019 Feb 15.

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan.

Background: Perforated diverticulitis with purulent peritonitis (Hinchey III diverticulitis) has traditionally been treated with a Hartmann's procedure in order to avoid the considerable postoperative morbidity and mortality associated with one-stage resection and primary anastomosis. Although there have been reports regarding laparoscopic lavage as the initial treatment of perforated Hinchey III diverticulitis, a formal treatment strategy has not been established yet. We performed a three-stage surgery, including laparoscopic lavage and drainage with diverting ileostomy (first stage), laparoscopic sigmoidectomy (second stage), and ileostomy closure (third stage) in a morbidly obese patient with Hinchey III diverticulitis.

Case Presentation: A 31-year-old man who presented with abdominal pain was diagnosed with perforated diverticulitis and sent to our hospital for evaluation. He had morbid obesity (body mass index (BMI) 50 kg/m), acute renal failure, and uncontrolled diabetes. We performed an emergency operation including laparoscopic lavage and drainage with a diverting ileostomy for this case of Hinchey III diverticulitis. Fifteen months after the first-stage surgery, we performed laparoscopic sigmoidectomy as the second stage. Finally, 5 months later, we performed ileostomy closure. The patient recovered without significant complications.

Conclusion: Three-stage surgery including early laparoscopic lavage and proximal diversion for morbidly obese, comorbid patients with Hinchey III diverticulitis may be indicated in the acute phase to avoid perioperative complications and permanent colostomy creation.
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http://dx.doi.org/10.1186/s40792-019-0588-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377691PMC
February 2019

Clinical Implication of the Relationship Between High Mobility Group Box-1 and Tumor Differentiation in Hepatocellular Carcinoma.

Anticancer Res 2018 Jun;38(6):3411-3418

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Background/aim: High mobility group box-1 (HMGB1) induces the release of proinflammatory cytokines and chemokines as a late-acting mediator of inflammation. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. However, little is known about the relationship between HCC and HMGB1 and its receptor RAGE (receptor for advanced glycation end products). This study analyzes the clinicopathological relevance of HMGB1 expression level and the effect of HMGB1 expression on the characteristics of HCC.

Materials And Methods: Samples from 75 HCC patients including 13 with positive hepatitis B surface antigen and 36 with hepatitis C antibody were studied. The expression of HMGB1 in paired cancer and non-cancerous tissues from patients with HCC was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and western blotting. Quantitative RT-PCR data were analyzed in association with the clinicopathological factors of patients with HCC.

Results: The expression of HMGB1 mRNA in HCC was high in well-differentiated tumors, but declined as tumors dedifferentiated to moderately and poorly differentiated HCC. The levels of HMGB1 mRNA showed a negative correlation with the presence of portal invasion (p=0.005) and the rise of serum PIVKA-II (p=0.034). There was no clear correlation between HMGB1 expression and proliferation activity of HCC using Ki-67 staining.

Conclusion: In HCC, HMGB1 expression level correlated inversely with tumor differentiation. The RAGE-HMGB1 interaction may play a greater role in the early stages of HCC tumorigenesis than during cancer development.
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http://dx.doi.org/10.21873/anticanres.12609DOI Listing
June 2018

Adenovirotherapy Delivering Cytokine and Checkpoint Inhibitor Augments CAR T Cells against Metastatic Head and Neck Cancer.

Mol Ther 2017 11 14;25(11):2440-2451. Epub 2017 Sep 14.

Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA. Electronic address:

In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-specific CAR T cells, which alone are insufficient to cure solid tumors. We tested multiple cytokines in conjunction with PD-L1-blocking antibody and found that Ad-derived IL-12p70 prevents the loss of HER2.CAR-expressing T cells at the tumor site. Accordingly, we created a construct encoding the PD-L1-blocking antibody and IL-12p70 (CAd12_PDL1). In head and neck squamous cell carcinoma (HNSCC) xenograft models, combining local treatment with CAd12_PDL1 and systemic HER2.CAR T cell infusion improved survival to >100 days compared with approximately 25 days with either approach alone. This combination also controlled both primary and metastasized tumors in an orthotopic model of HNSCC. Overall, our data show that CAd12_PDL1 augments the anti-tumor effects of HER2.CAR T cells, thus controlling the growth of both primary and metastasized tumors.
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http://dx.doi.org/10.1016/j.ymthe.2017.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675597PMC
November 2017

Clinical characteristics of breast cancer patients with mental disorders.

Breast 2017 Dec 21;36:39-43. Epub 2017 Sep 21.

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background: Severe mental disorders are thought to affect the diagnosis and treatment of breast cancer because of their lower awareness and understanding of the disease and their reduced ability to cooperate with medical staff. We analyzed the clinical features of patients with breast cancer and pre-existing mental disorders such as schizophrenia, dementia, and intellectual disability.

Patients And Methods: We reviewed the records of 46 patients who were diagnosed with schizophrenia, dementia, or intellectual disability, before being diagnosed with breast cancer. Three patients had more than 2 mental disorders. All patients underwent curative surgical treatment between September 1992 and January 2015. Patients' clinicopathological information was compared with a control group of 727 breast-cancer patients without mental disorders seen during the same period.

Results: Patients with mental disorders were less likely to be aware of their own breast cancer; the lesions were often found by other people such as family, care staff, and medical staff. Breast cancer patients with mental disorders had significantly more advanced T factors and overall stage at the time of surgery than their counterparts without mental illness, more patients underwent total mastectomy, and fewer patients underwent postoperative adjuvant chemotherapy and radiation. Biological markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression were not significantly different between groups. Disease-free survival and overall survival were not significantly different between groups.

Conclusion: Patients with mental disorders receive less postoperative adjuvant chemotherapy; however, their outcomes were not worse than those of patients without mental disorders.
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http://dx.doi.org/10.1016/j.breast.2017.08.010DOI Listing
December 2017

Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors.

Cancer Res 2017 04 24;77(8):2040-2051. Epub 2017 Feb 24.

Department of Medicine, Baylor College of Medicine, Houston, Texas.

Chimeric antigen receptor-modified T cells (CAR T cells) produce proinflammatory cytokines that increase expression of T-cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HD) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VEC) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HD exhibited no antitumor effect and CAd-VEC alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VEC with HER2.CAR T cells enhanced antitumor activity compared with treatment with either HER2.CAR T cells alone or HER2.CAR T cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VEC could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T cells and coadministration of Onc.Ad in an HER2 prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VEC combined with administration of tumor-directed CAR T cells to control the growth of solid tumors. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392365PMC
April 2017

Intraoperative Identification of the Parathyroid Gland with a Fluorescence Detection System.

World J Surg 2017 06;41(6):1506-1512

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.

Background: Intraoperative identification of the difficult-to-spot parathyroid gland is critical during surgery for thyroid and parathyroid disease. Recently, intrinsic fluorescence of the parathyroid gland was identified, and a new method was developed for intraoperative detection of the parathyroid with an original fluorescent detection apparatus. Here, we describe a method for intraoperative detection of the parathyroid using a ready-made photodynamic eye (PDE) system without any fluorescent dye or contrast agents.

Methods: Seventeen patients who underwent surgical treatment for thyroid or parathyroid disease at Kagoshima University Hospital were enrolled in this study. Intrinsic fluorescence of various tissues was detected with the PDE system. Intraoperative in vivo and ex vivo intrinsic fluorescence of the parathyroid, thyroid, lymph nodes and fat tissues was measured and analyzed.

Results: The parathyroid gland had a significantly higher fluorescence intensity than the other tissues, including the thyroid glands, lymph nodes and fat tissues, and we could identify them during surgery using the fluorescence-guided method. Our method could be applicable for two intraoperative clinical procedures: ex vivo tissue identification of parathyroid tissue and in vivo identification of the location of the parathyroid gland, including ectopic glands.

Conclusion: The PDE system may be an easy and highly feasible method to identify the parathyroid gland during surgery.
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http://dx.doi.org/10.1007/s00268-017-3903-0DOI Listing
June 2017

Clinical Significance of the Histoculture Drug Response Assay in Breast Cancer.

Anticancer Res 2016 11;36(11):6173-6178

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background/aim: Despite the fact that breast cancer patients are generally administered systemic chemotherapy after surgical treatment, predictive factors that allow optimization of chemotherapy are needed. The histoculture drug response assay (HDRA) is a clinically practical in vitro drug-response assay for identifying optimal anticancer agents.

Patients And Methods: Thirty-eight primary breast cancer patients who underwent surgical treatment without receiving systemic neoadjuvant therapy were analyzed. We retrospectively examined the relationships between clinicopathological factors and the HDRA results of 5 anticancer agents (mitomycin C (MMC), 5-fluorouracil (5-FU), doxorubicin hydrochloride (ADM), cisplatin (CDDP) and paclitaxel (PTX)).

Results: The relationships between the inhibition rates of anticancer drugs and clinicopathological factors were not significant, except for nuclear grade and venous invasion with the inhibition rate of 5-FU. We also established the threshold inhibition rate for PTX. The paclitaxel inhibition rate was significantly associated with disease-free survival (DFS).

Conclusion: HDRA results were independent from the clinicopathological factors of breast cancer patients demonstrating that individualized treatment is needed.
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http://dx.doi.org/10.21873/anticanres.11210DOI Listing
November 2016

Clinical and biological impact of cyclin-dependent kinase subunit 2 in esophageal squamous cell carcinoma.

Oncol Rep 2014 May 5;31(5):1986-92. Epub 2014 Mar 5.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima 890-8520, Japan.

Cyclin-dependent kinase subunit 2 (CKS2) is a cyclin-dependent kinase subunit (CKS) family member that participates in cell cycle regulation. Few studies have investigated its involvement in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to assess the clinical significance of CKS2 in ESCC. We used immunohistochemistry to study the clinicopathologic significance of CKS2 protein expression in 121 patients with ESCC. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we examined the expression of CKS2 mRNA in tumors and the corresponding normal esophageal tissues that were obtained from 62 patients. Finally, siRNA-mediated attenuation of CKS2 expression was examined in vitro. CKS2 protein expression was significantly correlated with depth of tumor invasion, clinical stage, lymphatic invasion and distant metastasis (p=0.033, 0.028, 0.041 and 0.009, respectively). CKS2 mRNA expression was higher in cancer tissue than in corresponding normal tissue (p<0.001). Patients with positive-CKS2 protein expression had a poorer five year survival frequency than patients who did not express CKS2 protein (p=0.025). In vitro, siRNA-mediated suppression of CKS2 slowed the growth rate of ESCC cells compared to control cells (p<0.001). The evaluation of CKS2 expression is useful for predicting the cause of malignant tumors and the prognosis of patients with ESSC.
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http://dx.doi.org/10.3892/or.2014.3062DOI Listing
May 2014

Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny.

J Transl Med 2014 Jan 27;12:27. Epub 2014 Jan 27.

Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background: Effective methods for eradicating cancer stem cells (CSCs), which are highly tumorigenic and resistant to conventional therapies, are urgently needed. Our previous studies demonstrated that survivin-responsive conditionally replicating adenoviruses regulated with multiple factors (Surv.m-CRAs), which selectively replicate in and kill a broad range of cancer-cell types, are promising anticancer agents. Here we examined the therapeutic potentials of a Surv.m-CRA against rhabdomyosarcoma stem cells (RSCs), in order to assess its clinical effectiveness and usefulness.

Methods: Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) is a marker of RSCs. We examined survivin mRNA levels, survivin promoter activities, relative cytotoxicities of Surv.m-CRA in RSC-enriched (serum-minus) vs. RSC-exiguous (serum-plus) and FGFR3-positive vs. FGFR3-negative sorted rhabdomyosarcoma cells, and the in vivo therapeutic effects of Surv.m-CRAs on subcutaneous tumors in mice.

Results: Both survivin mRNA levels and survivin promoter activities were significantly elevated under RSC-enriched relative to RSC-exiguous culture conditions, and the elevation was more prominent in FGFR3-positive vs. FGFR3-negative sorted cells than in RSC-enriched vs. RSC-exiguous conditions. Although Surv.m-CRA efficiently replicated and potently induced cell death in all populations of rhabdomyosarcoma cells, the cytotoxic effects were more pronounced in RSC-enriched or RSC-purified cells than in RSC-exiguous or progeny-purified cells. Injections of Surv.m-CRAs into tumor nodules generated by transplanting RSC-enriched cells induced significant death of rhabdomyosarcoma cells and regression of tumor nodules.

Conclusions: The unique therapeutic features of Surv.m-CRA, i.e., not only its therapeutic effectiveness against all cell populations but also its increased effectiveness against CSCs, suggest that Surv.m-CRA is promising anticancer agent.
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http://dx.doi.org/10.1186/1479-5876-12-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925355PMC
January 2014

Clinical significance of ¹⁸F-fluorodeoxyglucose positron emission tomography in superficial esophageal squamous cell carcinoma.

Ann Surg Oncol 2013 May 13;20(5):1646-52. Epub 2012 Dec 13.

Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Sakuragaoka, Kagoshima, Japan.

Purpose: To assess the clinical usefulness and significance of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in superficial esophageal squamous cell carcinoma (ESCC).

Methods: We examined FDG-PET for 80 consecutive patients with superficial ESCC without neoadjuvant treatment. Fifty-seven patients underwent radical esophagectomy, and 23 patients received endoscopic resection. The FDG uptake index was evaluated with clinicopathological findings, and glucose transporter 1 (Glut-1) expression in primary tumors was examined immunohistochemically.

Results: The FDG uptake in primary tumors correlated with histology, depth of tumor invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and Glut-1 expression. All patients with more than 4.4 maximum standardized uptake value (SUVmax) had deeper invasion of submucosa. Among 16 patients with lymph node metastasis, only two were found to have lymph node metastasis. FDG uptake, depth of tumor invasion, lymph node metastasis, and histology were found to be prognostic factors, and histology was an independent prognostic factor. In FDG uptake-positive patients, depth of tumor invasion and histology were prognostic factors.

Conclusions: FDG-PET is useful for diagnosing tumors with deeper invasion of submucosa and is helpful in making decisions regarding endoscopic treatment for superficial ESCC. Patients with FDG uptake-positive disease, deeper invasion of submucosa, poorly differentiated tumor, and poor prognosis should receive multimodal treatment.
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http://dx.doi.org/10.1245/s10434-012-2796-2DOI Listing
May 2013
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