Pancreatic cancer with liver metastasis maintaining complete response with gemcitabine monotherapy: A case report.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and it has a recurrence rate of >70%, even in resectable cases. The treatment strategy for recurrent PDAC involves systemic chemotherapy, with gemcitabine (GEM) monotherapy historically serving as the standard of care. The present study describes the case of a patient with PDAC and postoperative liver metastases that maintained clinical complete remission (cCR) for >7 years following GEM monotherapy. A 63-year-old woman with upper abdominal pain was diagnosed with resectable PDAC and underwent pancreaticoduodenectomy. The patient was treated with GEM + S-1 as adjuvant chemotherapy for 6 months. Multiple liver metastases were detected 15 months post-operation and the patient was administered GEM alone. After 12 cycles, computed tomography showed cCR and GEM monotherapy was discontinued after 15 cycles. The patient has had no signs or symptoms of recurrence >7 years after the first recurrence. In addition, the present study analyzed PDAC resection specimens from four patients, including this case, to determine the expression levels of hENT1 protein in the tumor tissues. hENT1 is a transmembrane protein that acts as a nucleoside transporter and is a major mediator of GEM uptake into human cells. In the present case, hENT1 staining exhibited low frequency and weak positivity in the central region, whereas a strong positive reaction was observed in nearly all cell membranes at the invasive front of the cancer. The location, intensity, and frequency of hENT1 staining varied among cases. In conclusion, the efficacy of GEM may be predicted prior to treatment by evaluating hENT1 expression.

Impact of Preoperative Tumor Size on Prognosis of Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinomas.

BACKGROUND: Tumor size (TS) is a well-established prognostic factor of pancreatic ductal adenocarcinoma (PDAC). However, whether a uniform treatment strategy can be applied for all resectable PDACs (R-PDACs) and borderline resectable PDACs (BR-PDACs), regardless of TS, remains unclear. This study aimed to investigate the impact of preoperative TS on surgical outcomes of patients with R-PDACs and BR-PDACs. METHODS: Chart data from three institutions were reviewed to select patients who underwent pancreatectomy for R-PDACs and BR-PDACs between January 2006 and December 2020. The patients were divided into TSsmall and TSlarge groups according to a TS cutoff value determined for each of R- and BR-PDAC using the minimum P value approach for the risk of R1 resection. RESULTS: TS of 35 mm and 24 mm was the best cutoff value in R-PDAC and BR-PDAC, respectively. The R1 rate was higher in the TSlarge than TSsmall group, in both R- (n = 35, 37% versus n = 294, 19%; P = 0.011) and BR-PDAC (n = 89, 37% versus n = 27, 15%; P = 0.030). Overall survival was significantly better in the TSsmall than TSlarge group in R-PDAC (38.2 versus 12.1 months; P < 0.001), but comparable between the two groups in BR-DPAC (21.2 versus 22.7 months; P = 0.363). Multivariate analysis revealed TS > 35 mm as an independent predictor of worse survival in patients with R-PDAC. CONCLUSION: Larger TS was associated with a higher R1 rate and is a worse prognostic factor in patients with R-PDAC.

Multimodal imaging findings of intrahepatic cholangiocarcinoma arising from a biliary adenofibroma: a case report with radiological-pathological correlation.

PURPOSE: Biliary adenofibroma is a solid microcystic epithelial neoplasm in the liver, comprising microcystic and tubuloacinar glandular tissues lined by a non-mucin secreting biliary epithelium and supported by a fibrous stroma. It is an extremely rare benign tumor with potential for malignant transformation. Herein, we report the case of a 64-year-old woman diagnosed with intrahepatic cholangiocarcinoma arising from biliary adenofibroma. METHODS: Imaging studies revealed a tumor of 50 mm diameter, consisting of two components in S1 of the liver. The ventral portion of the tumor showed an ill-defined mass with early peripheral and gradual centripetal enhancement invading to the middle hepatic vein on computed tomography (CT), diffusion restriction on magnetic resonance images, and high fluorine-18-2-deoxy-D-glucose (FDG) uptake on positron emission tomography, like conventional intrahepatic cholangiocarcinoma. The dorsal portion showed a well-defined and low-attenuated mass with heterogeneous early enhancement and partial wash-out on CT, marked hyperintensity on heavily T2-weighted images, and low FDG uptake. The patient subsequently underwent extended left hepatectomy. RESULTS: Pathologically, the former was diagnosed as cholangiocarcinoma and the latter as biliary adenofibroma. We discuss the radiological-pathological correlation of the tumor with a literature review. CONCLUSION: Preoperative diagnosis of biliary adenofibroma is extremely challenging; however, clinically, it is crucial not to miss the presence of malignant findings.

Prognosis of Pancreatic Cancer Based on Resectability: A Single Center Experience.

Although conversion surgery has increasingly been performed for initially unresectable advanced pancreatic ductal adenocarcinoma (PDAC), the rate of conversion, including that for patients who do not undergo resection, remains unclear. Patients with PDAC who were treated between January 2013 and December 2018 were classified into three groups: resectable (R), borderline resectable (BR), and unresectable (UR). We analyzed patient outcomes, including the rate of surgical resection and survival, in each of these groups. In total, 211 patients (R, 118; BR, 22; UR, 81) were selected. Among them, 117 (99%), 18 (82%), and 15 (19%) patients in the R, BR, and UR groups, respectively, underwent surgical resection. R0 resection rates were 88, 78, and 67%, whereas median overall survival (OS) from treatment initiation were 31, 18, and 11 months (p < 0.0001) in the R, BR, and UR groups, respectively. In patients who underwent surgical resection, relapse-free survival (RFS) and OS were similar among the three groups (R vs. BR vs. UR; median RFS (months), 17 vs. 13 vs. 11, p = 0.249; median OS (months), 31 vs. 26 vs. 32, p = 0.742). Lymph node metastases and incomplete adjuvant chemotherapy were identified as independent prognostic factors for OS. Although the surgical resection rate was low, particularly in the BR and UR groups, the prognosis of patients who underwent surgical resection was similar irrespective of the initial resectability status.

Therapeutic efficacy of dose-reduced adjuvant chemotherapy with S-1 in patients with pancreatic cancer: a retrospective study.

BACKGROUND: S-1 adjuvant chemotherapy is the standard treatment in Asia for resectable pancreatic ductal adenocarcinoma. The relative dose intensity of adjuvant chemotherapy influences survival in pancreatic cancer but does not precisely reflect treatment schedule modifications. We investigated the effects of total dose intensity of S-1 adjuvant chemotherapy on the survival of patients with pancreatic cancer and the permissible dose reduction. METHODS: Patients who underwent surgical resection during 2011-2019 for pancreatic cancer were selected. We determined the total dose intensity cut-off value that predicted tumor recurrence within 2 years postoperatively using receiver operating characteristic curves and compared the outcomes between the high and low total dose intensity groups. RESULTS: Patients with total dose intensity ≥ 62.5% (n = 53) showed significantly better overall survival than those with total dose intensity < 62.5% (n = 16) (median survival time: 53.3 vs. 20.2 months, P < 0.001). The median survival of patients without adjuvant chemotherapy (total dose intensity = 0, n = 28) was 24.8 months. Univariate analysis identified lymphatic involvement (P = 0.035), lymph node metastasis (P = 0.034), and total dose intensity (P < 0.001) as factors affecting survival. On multivariate analysis, total dose intensity (P < 0.001) was an independent predictor of worse survival. CONCLUSIONS: Maintaining a total dose intensity of at least 60% in S-1 adjuvant chemotherapy seems important to achieve a long postoperative survival in patients with pancreatic cancer.

Clinical Impact of Dual Time Point 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Fusion Imaging in Pancreatic Cancer.

We examined the value of preoperative dual time point (DTP) 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (FDG PET/CT) as a predictor of early recurrence or the outcomes in patients with pancreatic cancer. Standardized uptake values (SUVs) in DTP FDG PET/CT were performed as preoperative staging. SUVmax1 and SUVmax2 were obtained in 60 min and 120 min, respectively. ΔSUVmax% was defined as (SUVmax2 − SUVmax1)/SUVmax1 × 100. The optimal cut-off values for SUVmax parameters were selected based on tumor relapse within 1 year of surgery. Optimal cut-off values for SUVmax1 and ΔSUVmax% were 7.18 and 24.25, respectively. The combination of SUVmax1 and ΔSUVmax% showed higher specificity and sensitivity, and higher positive and negative predictive values for tumor relapse within 1 year than SUVmax1 alone. Relapse-free survival (RFS) was significantly worse in the subgroups of high SUVmax1 and high ΔSUVmax% (median 7.0 months) than in the other subgroups (p < 0.0001). The multivariate Cox analysis of RFS identified high SUVmax1 and high ΔSUVmax% as independent prognostic factors (p = 0.0060). DTP FDG PET/CT may effectively predict relapse in patients with pancreatic cancer. The combination of SUVmax1 and ΔSUVmax% identified early recurrent patient groups more precisely than SUVmax1 alone.

Effect of the response to preoperative treatment for hepatorenal syndrome on the outcome of recipients of living-donor liver transplantation.

BACKGROUND: The effect of pretransplant hepatorenal syndrome (HRS) on the outcomes of living-donor liver transplantation (LDLT) recipients with special reference to the recovery of HRS before LDLT was investigated. METHODS: The rate of HRS was 43.9% (125/285) among the cohort, and the subjects were divided into three groups: those without HRS (No-HRS group, n = 160), those with HRS but recovered following pretransplant renal function restoration treatment (Responders group, n = 55), and those with persistent HRS (Non-responders group, n = 70). RESULTS: While the 1-, 3-, and 5-year patient survival rates were comparable between those with and without HRS (89.6%, 84.7%, and 84.7% vs 95.6%, 92.2%, and 87.5%), the cumulative incidence of the development of posttransplant chronic kidney disease (CKD) was significantly higher in those with HRS (P < .001). In addition, there was a significant difference between Responders and Non-responders in the development of CKD (P = .01). In the Cox regression model, Non-responders (P = .032, HR 1.79 [95% C.I. 1.05-3.03]) and recipient age (P = .014, HR 1.62 [95% C.I. 1.10-2.37]) were independent predictors for the development of CKD after LDLT. CONCLUSION: Living-donor liver transplantation is safe and effective for patients with HRS, and CKD progression could be reduced among those with HRS who responded to renal restoration treatment.

Preoperative Rapid Weight Loss as a Prognostic Predictor After Surgical Resection for Pancreatic Cancer.

OBJECTIVE: The aim of the study is to evaluate the influence of cachexia at the time of diagnosis of pancreatic ductal adenocarcinoma (PDAC) on prognosis in patients undergoing surgical resection. METHODS: Patients with data on preoperative body weight (BW) change followed by surgical resection during 2008-2017 were selected. Large BW loss was defined as weight loss >5% or >2% in individuals with body mass index less than 20 kg/m2 within 1 year preoperatively. Influence of large BW loss, ΔBW defined as preoperative BW change (%) per month, prognostic nutrition index, and indices of sarcopenia. RESULTS: We evaluated 165 patients with PDAC. Preoperatively, 78 patients were categorized as having large BW loss. ΔBW was ≤ -1.34% per month (rapid) and > -1.34% per month (slow) in 95 and 70 patients, respectively. The median postoperative overall survival of rapid and slow ΔBW groups was 1.4 and 4.4 years, respectively (P < 0.001). In multivariate analyses rapid ΔBW (hazard ratio [HR], 3.88); intraoperative blood loss ≥430 mL (HR, 1.89); tumor size ≥2.9 cm (HR, 1.74); and R1/2 resection (HR, 1.77) were independent predictors of worse survival. CONCLUSIONS: Preoperative rapid BW loss ≥1.34% per month was an independent predictor of worse survival of patients with PDAC.

Co-expression of mesothelin and CA125/MUC16 is a prognostic factor for breast cancer, especially in luminal-type breast cancer patients.

The expression of mesothelin correlates with a poor prognosis in patients with breast cancer. Since mesothelin plays a role in cancer metastasis in association with CA125, we herein examined the expression of mesothelin and CA125, and the clinicopathological meaning and prognosis of the co-expression of mesothelin and CA125 in breast cancer. Our results showed that among 478 patients, mesothelin and CA125 were co-expressed in 48 (10 %), mesothelin only in 75 (16 %), CA125 only in 217 (45 %), and neither in 234 (49 %). A high correlation was observed between the expression of mesothelin and CA125 (P =0.0004). The co-expression of mesothelin and CA125 correlated with poor patient relapse-free survival (RFS) (P = 0.0001) and was identified as an independent predictor of RFS by Cox's multivariate analysis. In conclusion, this is the first to report the prognostic significance of the co-expression of mesothelin and CA125 in breast cancer. The co-expression of mesothelin and CA125 may be clinically useful for prognostication after surgical therapy in patients with breast cancer.

The Efficacy of S-1 as Adjuvant Chemotherapy for Resected Biliary Tract Carcinoma: A Propensity Score-Matching Analysis.

Even though S-1 is a widely used chemotherapeutic agent, there is no evidence for its use in an adjuvant setting for biliary tract carcinoma (BTC). Patients who underwent surgical treatment for BTC between August 2007 and December 2018 were selected. Propensity score matching was performed between patients who received S-1 as adjuvant chemotherapy (S-1 group) and those who underwent surgical treatment alone (observation group). Of 170 eligible patients, 38 patients were selected in each group after propensity score matching. Among those in the matched cohort, both the median recurrence-free survival (RFS) and overall survival (OS) in the S-1 group were significantly longer than those in the observation group (RFS, 61.2 vs. 13.1 months, p = 0.033; OS, not available vs. 28.2 months, p = 0.003). A multivariate analysis of the OS revealed that perineural invasion and adjuvant S-1 chemotherapy were independent prognostic factors. According to a subgroup analysis of the OS, the S-1 group showed significantly better prognoses than the observation group among patients with perineural invasion (p < 0.001). S-1 adjuvant chemotherapy might improve the prognosis of BTC, especially in patients with perineural invasion.

Sex differences in postsurgical skeletal muscle depletion after donation of living-donor liver transplantation, although minimal, should not be ignored.

BACKGROUND: Donor safety is the top priority in living-donor liver transplantation. Splenic hypertrophy and platelet count decrease after donor surgery are reported to correlate with the extent of hepatectomy, but other aftereffects of donor surgeries are unclear. In this study, we evaluated the surgical effects of donor hepatectomy on skeletal muscle depletion and their potential sex differences. METHODS: Among a total of 450 consecutive donor hepatectomies performed from April 2001 through March 2017, 277 donors who completed both preoperative and postoperative (60-119 days postsurgery) evaluation by computed tomography were the subjects of this study. Donors aged 45 years or older were considered elderly donors. Postoperative skeletal muscle depletion was assessed on the basis of the cross-sectional area of the psoas major muscle. Postoperative changes in the spleen volume and platelet count ratios were also analysed to evaluate the effects of major hepatectomy. RESULTS: The decrease in the postoperative skeletal muscle mass in the overall donor population was slight (99.4 ± 6.3%). Of the 277 donors, 59 (21.3%) exhibited skeletal muscle depletion (i.e., < 95% of the preoperative value). Multivariate analysis revealed that elderly donor (OR:2.30, 95% C.I.: 1.27-4.24) and female donor (OR: 1.94, 95% C.I. 1.04-3.59) were independent risk factors for postoperative skeletal muscle depletion. Stratification of the subjects into four groups by age and sex revealed that the elderly female donor group had significantly less skeletal muscle mass postoperatively compared with the preoperative values (95.6 ± 6.8%), while the other three groups showed no significant decrease. Due to their smaller physical characteristics, right liver donation was significantly more prevalent in the female groups than in the male groups (112/144, 77.8% vs 65/133, 48.9%; p < 0.001). The estimated liver resection rate correlated significantly with the splenic hypertrophy ratio (r = 0.528, p < 0.001) and the extent of the platelet count decrease (r = - 0.314, p < 0.001), but donor age and sex did not affect these parameters. CONCLUSION: Elderly female donors have a higher risk of postoperative skeletal muscle depletion. Additionally, female donors are more likely to donate a right liver graft, whose potential subclinical risks include postoperative splenic enlargement and a platelet count decrease.

Usefulness of preoperative drip infusion cholangiography with computed tomography for predicting surgical difficulty during laparoscopic cholecystectomy.

BACKGROUND: Drip infusion cholangiography with computed tomography (DIC-CT) is a major preoperative modality used for patients undergoing laparoscopic cholecystectomy (LC). METHODS: This study included 218 patients for whom preoperative DIC-CT images were obtained prior to undergoing LC. The association between gallbladder (GB) opacification in DIC-CT and the operative time was assessed. RESULTS: The GB opacification on the DIC-CT images was classified as follows: Grade 0, homogeneous opacification; Grade 1, heterogeneous opacification; Grade 2, only cystic duct can be identified; and Grade 3, no opacification. Images obtained for the 218 patients showed 41 (18.8%) with Grade 0, 91 (41.7%) with Grade 1, 54 (24.8%) with Grade 2, and 32 (14.7%) with Grade 3. The operative time and intraoperative blood loss were significantly longer and larger, respectively, in cases classified as Grade 2 or 3 (GB negative) compared with cases classified as Grade 0 or 1 (GB positive). We created an LC difficulty score based on the following variables that were significant independent predictors of increased operative time: GB negativity in DIC-CT (P = .002, 2 points), GB wall thickness (P = .002, 2 points), body mass index (P = .015, 1 point), preoperative alkaline phosphatase value (P = .018, 1 point), and preoperative C-reactive protein value (P = .04, 1 point). The LC difficulty score (Grade A, score 0-2; Grade B, score 3-5; and Grade C, score 6-7) was significantly associated with a prolonged operative time. CONCLUSION: Drip infusion cholangiography with computed tomography is useful for predicting the surgical difficulty of LC.

[Conversion Surgery after Etoposide/Cisplatin(EP)Therapy for Huge Pancreatic Neuroendocrine Carcinoma - A Case Report].

Neuroendocrine carcinoma(NEC)is known as rapid tumor growth, high grade malignancy and poor prognosis. We report a case of huge pancreatic NEC successfully performed conversion surgery after EP therapy. A 70-year-old female, was presented to our hospital with appetite loss. CT scan revealed huge tumor, 15 cm in diameter, locating at the pancreas with possible involvement to liver, stomach, common hepatic artery, left gastric artery and gastroduodenal artery. Peritoneal dissemination and para-aortic lymph node metastasis were also suspected. EUS-FNA showed neuroendocrine carcinoma with almost 100%positive staining rate of Ki-67. We immediately started etoposide/cisplatin(EP)therapy. After 6 courses of EP, the tumor shrank remarkably and peritoneal disseminations were disappeared. Common hepatic artery and gastroduodenal artery became free from the tumor. However, after 7 courses of EP, CT and PET-CT revealed tumor re-growth. Also renal impairment could not afford to continue EP therapy. Therefore we decided to perform conversion surgery. In the guideline in Japan, there is no content specialized for surgical treatment for NEC. Moreover, second-line of chemotherapy for NEC has not been established. In the future, accumulation of NEC cases will contribute to develop effective multidisciplinary treatment.

[Resection for the Recurrence of Hepatocellular Carcinoma in the Inferior Vena Cava and Right Atrium under Deep Hypothermic Circulatory Arrest].

A 77-year-old man underwent extended right lobectomy of the liver for rupture of hepatocellular carcinoma. Recurrence in the inferior vena cava andright atrium was noted 30 months after surgery. We performedextirpation of this tumor thrombosis under retrograde cerebral perfusion during deep hypothermic circulatory arrest. The pericardium was cut through sternotomy, and cooling was initiated. After cardiac arrest at 20.4°C, the inferior vena cava was separated. An incision was made in the right atrium andthe tumor thrombus was extirpated. In the meantime, brain protection was maintainedby retrograde cerebral perfusion. The patient was discharged on day 12 without postoperative complications. He remains alive 6 months after surgery without recurrence. This procedure prevented pulmonary embolism due to tumor thrombosis release. It was also possible to perform the procedure with retrograde cerebral perfusion.

[A Case of Pancreatic Metastasis from Pulmonary Pleomorphic Carcinoma].

We report a case of pancreatic metastasis of pulmonary pleomorphic carcinoma with duodenal invasion after left lower lobectomy. A 65-year-old male underwent left lower lobectomy for left lung cancer in 2016. The final pathological finding was a diagnosis is of pleomorphic carcinoma, pT2bN0M0, stageⅡA. The patient rejected postoperative chemotherapy for 10 months after lung surgery, and he was admitted to our hospital with poor oral intake. CT revealed that the tumor was located in the 2nd part of the duodenum, was about 7 cm in diameter, and was suspected to invade the superior mesenteric vein (SMV). Gastroendoscopy revealed whole-circumference stenosis at the 2nd part of the duodenum. The biopsy was suspicious of duodenal metastasis from pulmonary pleomorphic carcinoma. We scheduled pancreaticoduodenectomy with reconstruction of the portal vein. Regarding the intraoperative findings, the tumor was palpated at the 2nd part of the duodenum, and the tumor invaded the transverse colon and right urinary duct. The SMV had been invaded from the gastro-colic trunk to the root of the ileocolic vein. Therefore, pancreaticoduodenectomy, reconstruction of the portal vein with replacement of the graft of the left external iliac vein, right hemicolectomy, and right ureteral resection were performed. Regarding the pathological findings, the tumor existed in the pancreatic parenchyma and invaded the duodenal mucosa. The tumor cells were similar to those in a previous pulmonary pleomorphic carcinoma. The final pathological diagnosis was pancreatic metastases from pulmonary pleomorphic carcinoma. Surgical reports of metastatic pancreatic tumor have been observed sporadically; however, those reports were of pancreatic metastasis of renal cancer, and there are few reports of resection of pancreatic metastasis. This is a very valuable case of pancreatic metastasis from pulmonary pleomorphic carcinoma that could be resected.

[A Case of Pancreatic Head Neuroendocrine Tumor with Multiple Liver Metastases Successfully Treated with Multimodality Therapy IncludingRepeat Hepatectomy].

A 68-year-old man who had a history of bone marrow transplantation for acute myeloid leukemia was referred to our hospital due to an abnormal liver function test. Based on the clinical diagnosis of P-NET G2 with multiple livermetastases, pylorus-preserving pancreaticoduodenectomy with combined resection of the portal vein and liver sampling were performed (R2 resection). The resected specimen revealed NET-G2 tumorof the pancreatic head(Ki-67 proliferation index 5.0%)and hepatic metastasis(Ki-67 index 2.2%). Although CDDP/ETP(PE)and everolimus(AfinitorTM)regimen were started postoperatively, PE was discontinued due to bone marrow suppression. As the liver metastasis stayed SD for 4 months by everolimus single therapy, 6 hepatic metastases were resected for curative intent 5 months postoperatively. Thereafter, multiple liver metastases appeared 10 months after the metastasectomy. Everolimus single therapy was restarted. As the metastases were maintained SD for 4 months, repeat hepatectomy was performed for curative intent after right portal vein embolization. Multimodality therapy including repeat metastasectomy should be considered for selected patients with P-NET G2 with liver metastases for prolonged survival, if the operation can be performed with low perioperative morbidity.

Thermodynamics of the Thermal Denaturation of Acid Molten Globule State of Cytochrome c Indicate a Reversible High-Temperature Oligomerization Process.

In this study, we performed differential scanning calorimetry (DSC) and pressure perturbation calorimetry (PPC) analysis of the thermal transition of cytochrome c from an acidic molten globule (MG) state with the protein concentrations of 0.5-18.2 mg/mL. DSC profiles were highly reversible and showed clear protein-concentration dependence, indicating that reversible oligomerization occurred accompanying the thermal transition from the MG state. The DSC and PPC data required at least a six-state model (MG1 ⇄ MG2 ⇄ D ⇄ 1/2 I2 ⇄ 1/3 I3 ⇄ 1/4 I4) including three new oligomeric states: dimer (I2), trimer (I3), and tetramer (I4) in addition to the three monomeric states previously characterized. Dynamic light scattering confirmed the oligomerization during the thermal transition. The partial specific volumes of these oligomeric states were found to be smaller than those of the monomeric states, MG2 and D, indicating dehydration of hydrophobic surface or hydration of released anions may occur with the reversible oligomerization.

[Pancreaticoduodenectomy in a Patient with Severe Hyperbilirubinemia - A Case Report].

Although the safety of pancreaticoduodenectomy(PD)with hyperbilirubinemia has been reported, the permissible value of preoperative serum bilirubin is unknown. A 58-year-old man developed obstructive jaundice due to duodenal adenocarcino- ma. The initial serum bilirubin value was 26.8mg/dL, and preoperative biliary drainage was performed. However, the serum bilirubin value only decreased to 17.7mg/dL. The other liver function tests were normal. Therefore, we decided to perform PD despite persistent severe hyperbilirubinemia. The postoperative course was uneventful and the bilirubin value improved. He was discharged 17 days after the operation. In the present case, we safely performed PD despite severe jaundice after adequate preoperative liver function evaluation. The attempt to reduce the bilirubin value before surgery did not appear to affect the postoperative course.

Unusual Reversible Oligomerization of Unfolded Dengue Envelope Protein Domain 3 at High Temperatures and Its Abolition by a Point Mutation.

We report differential scanning calorimetry (DSC) experiments between 10 and 120 °C of Dengue 4 envelope protein domain 3 (DEN4 ED3), a small 107-residue monomeric globular protein domain. The thermal unfolding of DEN4 ED3 was fully reversible and exhibited two peculiar endothermic peaks. AUC (analytical ultracentrifugation) experiments at 25 °C indicated that DEN4 ED3 was monomeric. Detailed thermodynamic analysis indicated that the two endothermic peaks separated with an increasing protein concentration, and global fitting of the DSC curves strongly suggested the presence of unfolded tetramers at temperatures around 80-90 °C, which dissociated to unfolded monomers at even higher temperatures. To further characterize this rare thermal unfolding process, we designed and constructed a DEN4 ED3 variant that would unfold according to a two-state model, typical of globular proteins. We thus substituted Val 380, the most buried residue at the dimeric interface in the protein crystal, with less hydrophobic amino acids (Ala, Ser, Thr, Asn, and Lys). All variants showed a single heat absorption peak, typical of small globular proteins. In particular, the DSC thermogram of DEN4 V380K indicated a two-state reversible thermal unfolding independent of protein concentration, indicating that the high-temperature oligomeric state was successfully abolished by a single mutation. These observations confirmed the standard view that small monomeric globular proteins undergo a two-state unfolding. However, the reversible formation of unfolded oligomers at high temperatures is a truly new phenomenon, which was fully inhibited by an accurately designed single mutation.