Impact of Gemcitabine Plus S1 Neoadjuvant Chemotherapy on Borderline Resectable Perihilar Cholangiocarcinoma.

BACKGROUND: Surgical resection is the only curative strategy for perihilar cholangiocarcinoma (PHC), but recurrence rates are high even after purported curative resection. This study aimed to evaluate the efficacy and safety of gemcitabine/S-1 (GS) combination chemotherapy in the neoadjuvant setting. METHODS: In an open-label, single-arm, phase 2 study, neoadjuvant chemotherapy (NAC) with GS, repeated every 21 days, was administered for three cycles to patients with histologic or cytologically confirmed borderline resectable (BR) PHC who were eligible for inclusion in the study. In this study, BR PHC was defined as positive for lymph node metastasis and for cancerous vascular invasion or Bismuth type 4 on preoperative imaging. The primary end point consisted of the 3- and 5-year survival rates. The secondary end points were feasibility, resection rate, and pathologic effect. RESULTS: The study enrolled 60 patients between January 2011 and December 2016. With respect to toxicity, the major adverse effect was neutropenia, which reached grade 3 or 4 in 53.3% of cases. The overall disease control rate was 91.3%. The median survival time for the entire cohort was 30.3 months. For all the patients, the estimated 3-year survival rate was 44.1%, and the 5-year survival rate was 30.0%. Resection with curative intent was performed for 43 (71%) of the 60 patients. For 81% of the resected patients, R0 resection was performed, and Clavien-Dindo grade 3 complications or a higher morbidity rate was seen in 41% of the patients. The median survival time was 50.1 months for the resected and 14.8 months for the unresected patients. For the resected patients, the estimated 3-year survival rate was 55.8%, and the estimated 5-year survival rate was 36.4%. CONCLUSIONS: Gemcitabine/S-1 combination NAC has promising efficacy and good tolerability for patients with BR PHC.

Our Rationale of Initiating Neoadjuvant Chemotherapy for Hilar Cholangiocarcinoma: A Proposal of Criteria for "Borderline Resectable" in the Field of Surgery for Hilar Cholangiocarcinoma.

BACKGROUND: The concept of "borderline resectable" was recently introduced to the field of surgery for pancreatic cancer, and surgical outcomes for this disease with extremely dismal prognosis have improved since the introduction of this concept. However, no such concept has yet been introduced to the field of surgery for hilar cholangiocarcinoma (HCca). AIM: To determine a definition and criteria for "borderline resectable" in the field of surgery for HCca. PATIENTS AND METHODS: Retrospective analysis of 88 patients undergoing curative-intent surgery for HCca at our institution between May 1992 and December 2008 to clarify independent prognostic factors. RESULTS: Survival outcomes were obtained for these 88 patients, with a 5-year overall survival rate of 31.8%. Independent factors predictive of cancer death were determined by multivariate analysis to be the presence of regional lymph node metastasis (LNM) and pathological confirmed vascular invasion (VI). Cumulative survival rates of 23 patients with both LNM and VI who underwent surgery were significantly worse than those of the remaining 65 surgically treated patients and similar to those of 26 patients who were considered to have unresectable disease and treated with non-surgical multidisciplinary treatment during the same study period. CONCLUSION: Outcomes of surgery for cases of HCca showing regional LNM and VI were no better than those of non-surgical treatment for unresectable disease. Coexistence of these two factors indicates oncologically dismal condition and thus such cases should be considered "borderline resectable." Treatments additional to surgery are required for "borderline resectable" cases to obtain better outcomes.

Significance of Vascular Resection and Reconstruction in Surgery for Hilar Cholangiocarcinoma: With Special Reference to Hepatic Arterial Resection and Reconstruction.

PURPOSE: The aim of this study was to assess the efficacy of combined resection and reconstruction (CRR) of the hepatic artery (HA) in surgery for hilar cholangiocarcinoma (HC). MATERIALS AND METHOD: Among 172 patients who underwent surgical resection for HC, the following three groups were defined according to the type of vascular reconstruction: VR(-) group, in which neither CRR of the portal vein (PV) nor HA was performed (n = 74); VR-PV group, in which only CRR of the PV was required (n = 54); and VR-A group, in which CRR of the HA was performed either with or without CRR of the PV (n = 44). Clinicopathological variables and clinical outcomes were compared among the three groups. RESULTS: Although the VR-A group showed significantly more advanced disease than other groups, the R0 resection rate was comparable among the three groups (VR(-), 74 %; VR-PV, 80 %; VR-A, 80 %). The 5-year disease-specific survival rate was also comparable among the three groups (VR(-), 45.6 %; VR-PV, 51.2 %; VR-A, 22.3 %), but tended to be worse in the VR-A group than in the other groups. A similar trend was observed in morbidity rate. Lymph node metastasis was more frequent in the VR-A group (59 %) than in the other groups (VR(-), 33.8 %; VR-PV, 50 %). In the VR-A group, lymph node metastasis (p = 0.004) and adjuvant chemotherapy (p = 0.006) were determined to represent independent prognostic factors for survival according to multivariate analysis. CONCLUSION: CRR of the HA was considered efficacious in selected patients; however, long-term outcomes of the VR-A group seem unsatisfactory. Treatments additional to surgery may be necessary in cases requiring CRR of the HA.

Thrombomodulin improves rat survival after extensive hepatectomy.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. MATERIALS AND METHODS: Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group (n = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. RESULTS: All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival (P = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. CONCLUSIONS: rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration.

[Long-term survival of a breast cancer patient with liver metastasis treated with trastuzumab and Paclitaxel].

We report a long-term survival case of metastatic breast cancer treated with trastuzumab and paclitaxel. The patient was a 64-year-old female. She underwent right quadrantectomy with axillary lymphadenectomy for advanced breast cancer. Histological examination showed papillotubular carcinoma, f, t2, n1(6/14), ER(-), PgR(-), HER2(3+). CMF and radiation were performed as adjuvant therapy. One year after the operation she was diagnosed to have liver metastasis and initiated trastuzumab treatment. Paclitaxel was also intermittently administered when the tumor marker was elevated. Four years after the operation, she experienced obstructive jaundice and was diagnosed as hepatic portal region metastasis. Obstructive jaundice was promptly alleviated after receiving trastuzumab and vinorelbin. No adverse events were reported over sixty-eight months of trastuzumab treatment. Long-term trastuzumab and intermittent chemotherapy would be one of the optimal treatments for HER2-positive breast cancer.

Prophylactic drain management after pancreaticoduodenectomy without focusing on the drain fluid amylase level: A prospective validation study regarding criteria for early drain removal that do not include the drain fluid amylase level.

BACKGROUND/PURPOSE: Early drain removal (EDR) based on drain fluid amylase level (DFA) after pancreaticoduodenectomy excluded 15%-40% patients from EDR because of inappropriate DFA. METHODS: Of 198 pancreatoduodenectomy cases, we used the first 105 cases as an exploration cohort to construct the optimal criteria for EDR on postoperative day (POD)4 that were applied to the subsequent 93 cases used as the validation cohort. After that, we examined another 142 patients to further assess the efficacy of the new EDR criteria. RESULTS: Of the four independent predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) ([1] soft pancreas, [2] positive drain fluid culture on POD1, and [3] serum C-reactive protein [CRP] ≥13 mg/dL on POD4) in the exploration cohort, EDR was applied to cases in the validation cohort meeting the [2] and/or [3], enabling 96% (89/93) applicability of EDR. Outcomes were improved in the validation cohort compared to the exploration cohort; CR-POPF: 8.6% vs 25.7%, P = .005; Dindo-Clavien grade ≥ 3 complications: 23.7% vs 41.9%, P = .007; and median hospital stay (day): 21 vs 27, P = .005. The subsequent 142 patients showed 92% (131/142) applicability of EDR and 5.6% (8/142) incidence of CR-POPF. CONCLUSIONS: Our new criteria for EDR, without DFA, enabled ≥ 90% applicability of EDR and reduced CR-POPF.

A Simple and Easily Reproducible Model of Reversible Obstructive Jaundice in Rats.

BACKGROUND/AIM: Cholangiocarcinoma and pancreatic carcinoma are major malignancies that cause obstructive jaundice (OJ). This study aimed to develop a simple and easily reproducible rat model of reversible OJ (ROJ). MATERIALS AND METHODS: OJ was induced by clamping the common bile duct (CBD) using a U-shaped titanium hemoclip and its base was attached by ligation using 2-cm long 4-0 polypropylene suture. An anti-adhesive sheet was placed around the CBD. OJ was mitigated by pulling the suture to remove the clip under laparotomy 3 days later. Serum chemistry and liver histopathology were compared between the ROJ group and sham surgery (SH) groups. RESULTS: Three days after inducing OJ, serum total bilirubin, aspartate aminotransferase, and alanine aminotransferase were remarkably elevated in the ROJ group and thereafter reduced significantly after mitigating OJ. Similar findings were confirmed by histopathology. CONCLUSION: Our rat model of reversible OJ was considered simple and easily reproducible.

Single-institution experience with gemcitabine-cisplatin combination therapy as a second-line treatment for patients with unresectable biliary tract cancer after failure of gemcitabine-S-1 combination therapy: a prospective feasibility study.

BACKGROUND: NCCN and Japanese clinical guidelines for the treatment of biliary tract cancer (BTC) addressed gemcitabine-cisplatin combination (GC) as first-line chemotherapy for patients with advanced BTC ineligible for surgery in 2013. However, gemcitabine-S1 combination therapy (GS) has been widely used as first-line treatment in Japan because Japanese social insurance coverage of S-1 for BTC was approved prior to that of cisplatin. AIM: To elucidate the efficacy and tolerability of GC as second-line chemotherapy for patients with unresectable BTC after failure of GS. PATIENTS AND METHODS: Between September 2008 and August 2011, patients with unresectable BTC who provided informed consent and received GC comprising gemcitabine at 1000 mg/m2 and cisplatin at 20 mg/m2 given on days 1 and 8 in a 3-week cycle after failure of GS were included in the present study. Clinical data from these patients were collected prospectively. Primary endpoints were overall survival and time to progression (TTP). Secondary endpoints were response and tolerability. RESULTS: Twenty-seven patients were analyzed. Median survival time (MST) and TTP from the beginning of second-line treatment were 6.5 and 3.3 months, respectively, whereas MST from the commencement of first-line therapy was 12.06 months. One patient showed partial response, 16 had stable disease and 10 experienced disease progression. As a result, disease control rate was 63.0%. In total, 119 courses (median, 4; range, 1-15) were administered. Discontinuation of GC due to drug toxicities was not observed. CONCLUSION: Although some issues remain to be clarified, mainly due to the small sample size, this single-institution experience with GC as second-line treatment after failure of GS showed acceptable outcomes and good tolerability.

Solitary rib recurrence of hilar cholangiocarcinoma 10 years after resection: report of a case.

A 61-year-old female underwent right hemihepatectomy and caudate lobectomy for hilar cholangiocarcinoma in 1999. Ten years later, increasing serum carbohydrate 19-9 was detected by routine follow-up. Subsequent positron emission tomography revealed an asymptomatic lesion in the right 11th rib. As the mass steadily grew in size, the lesion was resected en bloc with the affected rib and muscle. The histopathological findings closely resembled those of the primary cholangiocarcinoma. Thus, the tumor was diagnosed as a metastatic recurrence 10 years after resection of the primary tumor. There have been a few reports of cholangiocarcinoma recurrence in long-term survivors at the surgical margins, peritoneum, or transhepatic drainage route. However, there are no reports of solitary extra-abdominal recurrence. This case highlights the need for careful follow-up of patients with cholangiocarcinoma and nodal metastasis, even in the absence of recurrence for >5 years after curative resection.