Publications by authors named "Kenzo Nakano"

12 Publications

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[Complete Remission of Metastatic Renal Cell Carcinoma with Invasion of the Duodenum and Pancreas after Treatment with Nivolumab Plus Ipilimumab Followed by Axitinib and Surgery : A Case Report].

Hinyokika Kiyo 2021 May;67(5):197-203

The Department of Urology, Kyoto University Hospital.

A man in his 60s was diagnosed with clear cell carcinoma of the right kidney with multiple lung metastases, tumor thrombus of the inferior vena cava (IVC), and invasion of the duodenum and pancreas. Ipilimumab plus nivolumab was administered as first-line therapy. After 3 treatment courses, computed tomography (CT) demonstrated a slight decrease in the size of the primary tumor and lung metastases. However, the patient became hemodynamically unstable due to persistent duodenal bleeding during treatment despite frequent blood transfusions. Axitinib was then initiated as second-line therapy. The duodenal bleeding ceased 10 days after starting axitinib and his anemia remissed. Subsequent CT showed further decrease in the size of the primary tumor and lung metastases. The patient underwent right nephrectomy after improvement of nutrition. IVC thrombectomy, and pancreaticoduodenectomy. The lung metastases disappeared on postoperative imaging and no additional treatment was provided. Twelve months after surgery, he was in good health and showed no signs of recurrence.
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http://dx.doi.org/10.14989/ActaUrolJap_67_5_197DOI Listing
May 2021

Impact of vascular abnormality on contrast-enhanced CT and high C-reactive protein levels on postoperative pancreatic hemorrhage after pancreaticoduodenectomy: A multi-institutional, retrospective analysis of 590 consecutive cases.

Pancreatology 2021 Jan 1;21(1):263-268. Epub 2020 Dec 1.

Department of Surgery, Division of Hepato-biliary-pancreatic Surgery and Transplantation, Kyoto University, Japan.

Background: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy.

Methods: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis.

Results: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT.

Conclusion: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH.
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http://dx.doi.org/10.1016/j.pan.2020.11.007DOI Listing
January 2021

Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress.

Endocr Relat Cancer 2020 07;27(7):431-439

Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.
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http://dx.doi.org/10.1530/ERC-20-0028DOI Listing
July 2020

Risk factors for short recurrence-free survival after resection of pancreatic neuroendocrine tumor (PanNET) liver metastases: which patients should undergo resection?

Scand J Gastroenterol 2020 Apr 30;55(4):479-484. Epub 2020 Mar 30.

Department of Surgery, Kyoto University, Kyoto, Japan.

In the treatment of metastatic pancreatic neuroendocrine tumors (PanNETs), surgical resection is the first choice if curative resection is expected. However, most patients develop recurrence after resection of liver metastasis. Because one of the benefits of resection is to gain a tumor-free period for the patients, it is important to identify which patients achieve longer recurrence-free survival (RFS) by resection. In this study, the clinicopathological factors associated with RFS after resection of metastatic PanNETs in the liver were evaluated to identify the patient group that is suitable for resection. Consecutively diagnosed patients with PanNET liver metastasis with resection at our hospital from January 2000 to July 2019 were evaluated. A total of 26 metastatic PanNET patients with primary liver resections were evaluated. The median follow-up time was 48.3 months. There were 18 NET recurrences of the total 26 resections, with a median RFS of 17.9 months. Independent risk factors for short RFS were a high Ki67 index ( = .009) and the number of resected tumors ( = .045). When the cut-off value for the Ki67 index was 5.0% and that for the number of resected tumors was 6, Ki67 > 5.0% tumors had shorter RFS (4.9 months vs. 38.2 months  = .006), and patients with tumors > = 7 tumors had shorter RFS (4.7 months vs. 27.5 months  = .001). These findings indicate that good candidates for resection of metastatic tumors of PanNETs could be patients with low Ki67 tumors and a small number of metastatic tumors.
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http://dx.doi.org/10.1080/00365521.2020.1743352DOI Listing
April 2020

Usefulness of F-FDG-PET/CT in the diagnosis and prediction of recurrence of pancreatic neuroendocrine neoplasms.

J Hepatobiliary Pancreat Sci 2020 Jul 14;27(7):414-420. Epub 2020 May 14.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan.

Background: Although F-FDG-PET/CT is a widely used diagnostic tool for several malignancies, its efficacy in diagnosing pancreatic neuroendocrine tumors is reported to be controversial because of the short-term follow-up.

Methods: We retrospectively compared demographics and pathological features between F-FDG-positive and -negative diseases. Additionally, we evaluated whether the avidity of F-FDG-PET/CT affected earlier recurrence after curative treatment of non-functioning tumors. The median duration of observation was 65.6 months.

Results: Seventy-two patients were enrolled. F-FDG-positive diseases were pathologically advanced and significantly associated with metastatic behavior. In a multivariate analysis, metastatic behavior and WHO tumor grade was independently associated with F-FDG accumulation. Only 25% of functional tumors (4/16) and 8% of insulinomas (1/12) were F-FDG-positive. In a Kaplan-Meier analysis in patients with non-functioning tumors (n = 56), F-FDG-positivity was significantly correlated with poorer recurrence-free survival (RFS) but had no correlation with overall survival. In univariate analysis of factors associated with shorter RFS, male gender, prevalence of nodal metastasis, WHO tumor grade ≥G2, or F-FDG-positive disease were significantly higher in patients with shorter RFS, whereas only F-FDG-positivity was associated with shorter RFS in multivariate analyses.

Conclusions: The avidity of F-FDG-PET/CT was associated with metastatic behavior of pancreatic neuroendocrine tumors and recurrence after treatment of non-functioning tumors.
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http://dx.doi.org/10.1002/jhbp.734DOI Listing
July 2020

Combination of postoperative C-reactive protein value and computed tomography imaging can predict severe pancreatic fistula after pancreatoduodenectomy.

HPB (Oxford) 2020 02 12;22(2):282-288. Epub 2019 Aug 12.

Department of Surgery, Division of Hepatobiliarypancreatic Surgery and Transplantation, Kyoto University, Japan.

Background: Recent management after pancreatoduodenectomy recommends either omission of prophylactic drainage or early removal. This potentially makes the diagnosis of postoperative pancreatic fistula (POPF) difficult because the diagnosis is based on the amylase value of drain effluent. The aim of this study was to determine if severe POPF could be predicted independent of drainage information.

Methods: Records of consecutive patients who underwent pancreatoduodenectomy between 2012 and 2018 were included for further analysis. The presence of a peripancreatic collection (PC) on routine postoperative (day7) computed tomography (early CT) and perioperative characteristics were analyzed.

Results: PC appeared in 82/211 patients (39%) and was associated with clinically relevant POPF (p < 0.001). The C-reactive protein (CRP) on postoperative day5 was a good predictor of severe POPF (needing interventional therapy or Grade C) (area under the receiver operating characteristics curve, 0.802; 95% confidence interval, 0.702-0.875). Presence of a PC and a high CRP value were independent risk factors for severe POPF following multivariate analysis. The combination of CRP<5.0 mg/dL on postoperative day 5 and the absence of a PC had 98% negative predictive value.

Conclusion: The combination of CRP measurement and PC evaluation by early CT was useful in predicting severe POPF after pancreatoduodenectomy.
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http://dx.doi.org/10.1016/j.hpb.2019.06.020DOI Listing
February 2020

Predictive value of the Ki67 index for lymph node metastasis of small non-functioning pancreatic neuroendocrine neoplasms.

Surg Today 2019 Jul 5;49(7):593-600. Epub 2019 Mar 5.

Department of Surgery, Kyoto University, 54 Shogoin, Kawaracho, Sakyo, Kyoto, 606-8507, Japan.

Background: We evaluated the clinicopathological factors associated with lymph node metastasis in patients with non-functioning pancreatic neuroendocrine neoplasms (PanNENs), focusing on the risk factors and range of lymph node metastasis for tumors ≤ 2 cm in diameter.

Methods: The subjects of this study were patients with PanNENs consecutively diagnosed at our hospital between January, 2000 and June, 2018. We analyzed 69 patients who underwent R0 resection of a non-functioning sporadic PanNEN with no distant metastasis, as well as 43 patients with tumors ≤ 20 mm in radiological diameter.

Results: Nineteen patients (27.5%), including 7 (16.3%) with a small PanNEN, had lymph node metastasis. A large radiological diameter, a high Ki67 index, and cyst formation correlated significantly with positive lymph node metastasis. In patients with tumors ≤ 20 mm in diameter, a high Ki67 index correlated significantly with lymph node metastasis. When we set the cut-off Ki67 index as 3.3%, 2 of 43 patients had lymph node metastasis. Tumors in the uncinate process readily metastasized to the region around the superior mesenteric artery.

Conclusions: These findings suggest that a high Ki67 index indicates a risk of lymph node metastasis for tumors ≤ 20 mm in diameter and that lymphadenectomy should be performed in the region spatially adjacent to the primary tumor.
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http://dx.doi.org/10.1007/s00595-019-01779-9DOI Listing
July 2019

A Prospective Study of Intensity-modified Radiation Therapy in Comparison with Conventional 3D-RT for BR Pancreatic Cancer Patients with Arterial Involvement.

Anticancer Res 2017 12;37(12):7023-7030

Department of Surgery, Kyoto University, Kyoto, Japan.

Background/aim: Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that allows accurate irradiation with reduced damage to surrounding tissues. Here, we analyzed borderline-resectable pancreatic cancer (BRPC) with arterial abutment (BR-A) patients with IMRT as neoadjuvant therapy and performed comparisons with patients with conventional RT to clarify the advantages of IMRT as a neoadjuvant therapy.

Patients And Methods: Thirty BR-A patients treated at our hospital between January 2012 and December 2015 were divided into two groups: 12 patients underwent conventional 3D-RT before resection (RT group); and 18 patients underwent IMRT before resection (IMRT group). We analyzed safety, tumor resection rate, histological classification of the tumor and overall survival.

Results: The R0 rate was 84% for the IMRT group and 83% for the RT group. Local therapeutic effects as assessed by Evans classification showed a higher local control rate in the IMRT group (Grade: 1, 0%; 2a, 25%; 2b, 41.6%; 3, 17%; 4, 8%) than in the RT group (Grade: 1, 17%; 2a, 50%; 2b, 17%; 3, 17%; 4, 0%). The cumulative dose of S1 treatment as adjuvant therapy was much smaller in the RT group (18.3%) compared to that in the IMRT group (57.1%, p=0.047), and with better subsequent overall survival rate (MST 32 months vs. 13.8 months, p=0.0273).

Conclusion: The IMRT group showed a better control rate than the RT group. The neoadjuvant IMRT has advantages of higher completion rate of adjuvant chemotherapy with better nutritional status and better subsequent overall survival rate (OS).
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http://dx.doi.org/10.21873/anticanres.12172DOI Listing
December 2017

Comparison of Recurrence Between Pancreatic and Duodenal Neuroendocrine Neoplasms After Curative Resection: A Single-Institution Analysis.

Ann Surg Oncol 2018 Feb 21;25(2):528-534. Epub 2017 Nov 21.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan.

Background: The primary site of a neuroendocrine neoplasms (NEN) around the head of the pancreas is sometimes difficult to assess before resection, and the characteristics of the primary site around this region have not been elucidated for recurrence after curative resection. In this study, the clinicopathologic characteristics of pancreatic NEN (PanNEN) and duodenal NEN (DuNEN) were evaluated, and the risk factors as well as the recurrence types after resection were investigated.

Methods: Consecutively diagnosed NEN patients at the authors' hospital from January 2000 to July 2016 were evaluated in this study. For 117 PanNEN patients and 31 non-ampullary DuNEN patients, R0 resection was achieved. The median follow-up period was 8.1 years.

Results: In this study, 27 PanNEN patients (23.1%) had recurrences, with a median disease-free survival (DFS) of 133 months, whereas 11 DuNEN patients (35.5%) had recurrences, with a median DFS of 156 months. The PanNEN patients tended to have primary recurrence in the liver (85.2%), followed by lymph nodes (11.1%). The independent risk factors for short DFS were lymph node metastasis at resection (p = 0.001) and microvascular invasion (p = 0.048). In contrast, the DuNEN patients were likely to have lymph node metastasis (81.8%). The independent risk factors for short DFS were lymph node metastasis at resection (p = 0.003) and large diameter (p = 0.013).

Conclusions: Most initial recurrences of PanNEN occurred in the liver, whereas those of DuNEN appeared in lymph nodes, suggesting that proper diagnosis of the primary site and appropriate imaging methods for surveillance after resection are necessary.
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http://dx.doi.org/10.1245/s10434-017-6260-1DOI Listing
February 2018

A case of successful conversion from everolimus to surgical resection of a giant pancreatic neuroendocrine tumor.

Surg Case Rep 2017 Dec 20;3(1):82. Epub 2017 Jul 20.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin. Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Although pancreatic neuroendocrine tumors generally have a far better prognosis relative to pancreatic cancer, the varied manifestations lead to treatment-related challenges. Everolimus therapy is generally recommended for patients with advanced pancreatic neuroendocrine tumors; however, its efficacy in a neoadjuvant setting remains unclear. Here we present a case of a giant pancreatic neuroendocrine tumor with a portal tumor thrombus that became resectable after everolimus therapy.

Case Presentation: A 62-year-old woman was admitted to our hospital for surgical resection of a giant pancreatic neuroendocrine tumor in the left upper abdomen. Unfortunately, she was ineligible for surgery because the tumor had extended near the hepatic hilus in the portal vein, and she was administered everolimus (10 mg/day). After 2 years of this therapy, the extent of portal vein involvement had decreased, despite the lack of significant changes in the tumor size, and the hepatic hilus became free of disease. She was subsequently referred to us for resection via distal pancreatectomy with portal vein reconstruction because the tumor had begun to grow slowly. Pathological review identified a grade 2 neuroendocrine tumor with no lymph node metastasis. The patient's postoperative course was uneventful, and she has remained recurrence-free for 27 months, despite a lack of additional treatment.

Conclusions: Our experience suggests that everolimus could be useful for neoadjuvant therapy in cases of locally advanced pancreatic neuroendocrine tumor.
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http://dx.doi.org/10.1186/s40792-017-0361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519517PMC
December 2017

Abdominal contamination with Candida albicans after pancreaticoduodenectomy is related to hemorrhage associated with pancreatic fistulas.

Pancreatology 2017 May - Jun;17(3):484-489. Epub 2017 Mar 18.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Japan.

Background/objectives: Pancreatic fistulas are one of the most frequent morbidities after pancreaticoduodenectomy. Several reports have suggested a relationship between bacterial infections and postoperative pancreatic fistulas, although details of the mechanisms involved in hemorrhage in association with the fistulas have not been elucidated. This study retrospectively examined the relationship between positive drainage culture and hemorrhage associated with pancreatic fistulas after pancreaticoduodenectomy.

Methods: From January 2012 to December 2015, 142 consecutive patients underwent pancreaticoduodenectomy at our institution. We retrospectively reviewed the patients' demographic data, perioperative laboratory data, and drainage culture results.

Results: Twenty-four (17%) patients had clinically relevant postoperative pancreatic fistulas, whereas thirty-four (24%) patients experienced positive drainage culture. Multivariable analysis revealed that positive drainage culture was independently associated with clinically relevant postoperative pancreatic fistulas (odds ratio, 18.1; 95% confidence interval, 5.5-72.2; P < 0.001). Additionally, the prevalence of Candida albicans in the lavage of eight patients significantly correlated with hemorrhage associated with pancreatic fistulas (odds ratio, 43.5; 95% confidence interval, 6.2-513.3; P < 0.001). Seventy-five percent (6/8) of these patients suffered potentially lethal hemorrhagic complications and needed intervention.

Conclusions: A positive abdominal drainage culture is associated with the development of pancreatic fistulas. Moreover, the presence of Candida albicans in drainage fluid may be a risk factor for hemorrhagic complications.
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http://dx.doi.org/10.1016/j.pan.2017.03.007DOI Listing
March 2018

Concurrent gemcitabine+S-1 neoadjuvant chemotherapy contributes to the improved survival of patients with small borderline-resectable pancreatic cancer tumors.

Surg Today 2016 Nov 9;46(11):1282-9. Epub 2016 Feb 9.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo, Kyoto, 606-8507, Japan.

Purposes: In the surgical treatment of pancreatic cancer, margin-negative status is one of the most important determinants of survival. We conducted this study to explore surgical margin status as well as other factors affecting the survival of borderline-resectable pancreatic cancer (BRPC) patients who received neoadjuvant chemotherapy with gemcitabine and S-1.

Methods: Eighteen BRPC patients were prospectively treated with concurrent gemcitabine and S-1 neoadjuvant chemotherapy (NAC+) and 15 of these patients underwent resection. We evaluated the safety and efficacy of this treatment regimen by comparing the outcomes of these patients with those of 19 BRPC patients who did not receive neoadjuvant chemotherapy (NAC-) during the same period.

Results: Fifteen (83 %) of the NAC+ patients underwent pancreatectomy. The remaining three patients (17 %) had regional tumor progression or liver metastasis. Of the 15 NAC+ patients who underwent resection, 3 (20 %) had margin-positive status, whereas 9 of the 19 (43 %) NAC- patients had margin-positive status (p = 0.002). However, disease-free survival and overall survival were similar in the two groups (MST 21.7 vs. 21.1 months). NAC+ patients with tumors smaller than 30 mm had favorable overall survival (MST 43.9 vs. 23.1 months, p = 0.0321). Most recurrences developed at distant sites rather than locally in both groups.

Conclusions: In the neoadjuvant setting, gemcitabine and S-1 improved the negative surgical margin rate in BRPC patients, but it did not improve survival. Thus, neoadjuvant chemotherapy should be given to BRPC patients at an earlier stage.
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http://dx.doi.org/10.1007/s00595-016-1310-zDOI Listing
November 2016
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