Extended hepatic resection for gallbladder cancer

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1 The American Journal of Surgery 194 (2007) Clinical surgery American Extended hepatic resection for gallbladder cancer Srinevas K. Reddy, M.D.*, Carlos E. Marroquin, M.D., Paul C. Kuo, M.D., M.B.A., Theodore N. Pappas, M.D., Bryan M. Clary, M.D. Division of General Surgery, Department of Surgery, Duke University Medical Center, Box 3247, Durham, NC 27710, USA Manuscript received January 12, 2007; revised manuscript February 1, 2007 Abstract Background: Although radical cholecystectomy is the standard of care for gallbladder cancers that invade perimuscular connective tissue or perforate visceral peritoneum, the role of extended right hepatectomy in achieving negative resection margins is not clear. Methods: Clinicopathologic, perioperative, and long-term outcome data were reviewed from patients who underwent hepatic resection for gallbladder cancer. Results: From 1995 to 2005, 22 consecutive patients underwent hepatic resection for gallbladder cancer, and 11 underwent extended hepatectomy. Negative resection margins were achieved in all patients. There were no significant differences in postoperative morbidity, mortality, and long-term survival after extended and minor hepatectomy. T3 tumors negatively predicted overall and recurrence-free survival. Comments: Extended hepatectomy achieves negative resection margins for patients with gallbladder cancer and is associated with acceptable morbidity and long-term survival Excerpta Medica Inc. All rights reserved. Keywords: Extended liver resection; Gallbladder cancer; Radical cholecystectomy Traditionally, gallbladder cancer has been associated with poor prognosis because the lack of recognized symptoms results in advanced primary and nodal disease at presentation. The aggressive biologic nature of this tumor, coupled with extensive lymphatic drainage of the gallbladder, often results in rapid progression of disease. However, several recent studies have reported long-term patient survivors after margin negative resection of stages III and IV disease [1 6]. Although the infrequent incidence of gallbladder cancer likely precludes any randomized controlled trials, the consensus from large case series is that a simple cholecystectomy is sufficient therapy for T1 (tumor that invades the lamina propria or muscle layer) node-negative disease. A radical cholecystectomy, involving a 4B/5 segment resection, and portal lymphadenectomy has been established as the minimum therapy for T2 (invasion of perimuscular connective tissue) and T3 (perforation of visceral peritoneum) tumors because of the relatively high likelihood of direct hepatic invasion and nodal disease [1,5]. Although a radical cholecystectomy allows for an adequate margin near the gallbladder fundus, it results in a minimal margin at the * Corresponding author. Tel.: or ; fax: address: reddy005@mc.duke.edu base of the cystic plate and thus may not be sufficient for tumors that lie near the gallbladder neck, in Hartmann s pouch, or that extend into the triangle of Calot [1]. The role of extended hepatectomy, where the plane of transection is well to the left of the cystic plate, in decreasing local or regional recurrence and prolonging long-term outcome is not well defined. The objective of this study was to report our experience with hepatic resection for gallbladder cancer, with a focus on the safety and long-term outcomes of extended hepatectomy, for patients suspected to have disease near the cystic plate. Methods After obtaining approval from the Institutional Review Board at Duke University Medical Center, patients who underwent hepatic resection for gallbladder cancer from August 1995 to December 2005 were identified from a prospective hepatectomy database. After 2001, patients who were discovered to have gallbladder cancer due to an incidental finding on pathologic specimen examination after simple cholecystectomy or on preoperative diagnostic imaging were evaluated for extended right hepatectomy as the procedure of choice for definitive surgical resection. We typically performed an extended hepatectomy in the following circumstances: (1) when the cystic duct margin of the /07/$ see front matter 2007 Excerpta Medica Inc. All rights reserved. doi: /j.amjsurg

2 356 S.K. Reddy et al. / The American Journal of Surgery 194 (2007) previous cholecystectomy specimen was positive or unknown, (2) after open cholecystectomy or when the initial operative indication was acute cholecystitis because we anticipated that the triangle of Calot would be obliterated by scar tissue, (3) when node-positive disease was evident before hepatic resection (either in the initial cholecystectomy specimen or detected on preoperative imaging), (4) for patients presenting with preoperative jaundice because of biliary obstruction, and/or (5) for large-mass lesions detected on preoperative imaging (usually computed axial tomography [CAT]). Patients without any of these criteria were offered minor hepatic resection (segment 4B/5 hepatectomy). Patients 75 years old and those with extensive medical comorbidity were not offered extended hepatectomy. Portal vein embolization (PVE) was used when the estimated volume of the future liver remnant was 25% of the native liver volume or in cases of severe steatosis (as detected by CAT scan). A retrospective review of patient demographics, tumor characteristics, surgical treatment, length of hospital stay, postoperative course, use of adjuvant chemotherapy or radiotherapy, and long-term outcomes was completed. Operative mortality included any death attributed to liver resection (as determined by the operative surgeon) and all death within 30 days of partial hepatectomy. Deaths were ascertained by clinic or hospital records, the Social Security Death Index, and the Institutional Review Board Tumor Registry. Overall survival reflected deaths from any cause. The last date of any clinical correspondence was used to determine length of recurrencefree survival after hepatectomy. Statistical analyses were performed using the Stats Direct, Version (StatsDirect Limited Software, Cheshire, UK) and GraphPad Prism, Version 3.0 (GraphPad Software, San Diego, CA) software packages. Categoric variables were summarized with percentages. Continuous variables were summarized with medians and corresponding ranges. Comparisons between categoric variables were performed with Fisher s exact test. Mann-Whitney U test was used to compare continuous variables. Survival was estimated with Kaplan-Meier analysis and compared with the log-rank test. Two-sided mid-p values are reported; P.05 was considered significant. Tumor staging was reported according to the American Joint Committee on Cancer 6th edition TNM staging guidelines [7]. Specifically, T1 tumors invade the gallbladder lamina propria or muscle layers; T2 lesions invade perimuscular connective tissue without extension into liver; T3 tumors perforate visceral peritoneum and/or directly invade the liver or 1 other adjacent organ; and T4 carcinomas invade the main portal vein, hepatic artery, or multiple extrahepatic organs. Any node-positive disease was designated as N1. Results From 1995 to 2005, 22 consecutive patients underwent curative hepatic resection for gallbladder cancer. Eleven of 22 (50%) patients underwent extended hepatectomy. Three patients operated on after 2001 were not offered extended hepatectomy because of old age ( 75 years). Indications for extended hepatectomy included large tumor size in patients who did not undergo previous simple Table 1 Tumor characteristics, treatments, and outcomes Stage Liver resection BDE Previous chol Pathology Grade Adjuvant therapy Status (mo) T 3 N 1 Extended right hepatectomy N N Adenoca Poor Y DOD (11) T 3 N 1 Extended right hepatectomy Y Y Adenoca Well Y NED (27) T 3 N 1 Extended right hepatectomy Y Y Adenoca Poor Y DOD (4) T 3 N 1 Extended right hepatectomy Y Y Adenoca NA N NED (24) T 3 N 0 Extended right hepatectomy N N Adenoca Poor N DOD (5) T 3 N 0 4B/5 bisegmentectomy N Y Adenoca Poor Y DOD (10) T 3 N 0 Extended right hepatectomy Y Y Adenoca Poor Y DOD (52) T 3 N 0 Extended right hepatectomy N N Squamous Poor Y NED (48) T 3 N 0 4B/5 bisegmentectomy Y Y Adenoca Well Y DOD (62) T 3 N 0 Extended right hepatectomy Y N Adenoca Moderate N DOD (24) T 3 N 0 4B/5 bisegmentectomy N Y Adenoca Moderate N POD (1) T 3 N 0 4B/5 bisegmentectomy Y Y Adenoca Poor N NED (30) T 2 N 1 4B/5 bisegmentectomy Y Y Adenoca Moderate Y NED (52) T 2 N 1 Extended right hepatectomy Y Y Adenoca Well Y NED (67) T 2 N 0 4B/5 bisegmentectomy Y Y Adenoca Moderate Y DOD (62) T 2 N 0 4B/5 bisegmentectomy N Y Adenoca Well Y DOC (45) T 2 N 0 4B/5 bisegmentectomy N Y Adenoca Well Y NED (107) T 2 N 0 4B/5 bisegmentectomy N N Papillary Moderate N NED (37) T 2 N 0 Extended right hepatectomy Y Y Adenoca Well N NED (26) T 2 N 0 Extended right hepatectomy Y Y Papillary Moderate N AWD (14) T 2 N 0 4B/5 bisegmentectomy N Y Adenoca Well Y NED (18) T 1 N 0 4B/5 bisegmentectomy N N Papillary Well N NED (12) Note: Numeric data in status column refers to number of months from partial hepatectomy to date of death, disease recurrence, or last date of follow-up for patients who had NED. Adjuvant therapy refers to either chemotherapy or external beam radiation therapy. Adenoca adenocarcinoma; AWD alive with disease; BDE bile duct excision; chol cholecystectomy; DOC dead of other causes; DOD dead of disease; NED no evidence of disease; POD postoperative death.

3 S.K. Reddy et al. / The American Journal of Surgery 194 (2007) cholecystectomy (n 5), positive or unknown cystic duct margin status after simple cholecystectomy (n 4), preoperative biliary obstruction (n 1), known nodepositive disease before hepatic resection (n 4), and acute cholecystitis leading to simple cholecystectomy (n 1). The median age of all patients was 54 (range 45 to 80) years, and 15 of 22 (68%) were women. Table 1 lists tumor characteristics, treatments, and outcomes for each patient. Most patients, ie, 16 of 22 (73%), presented for curative treatment after previous laparoscopic cholecystectomy. Four of 11 (36%) patients underwent preoperative PVE. All patients underwent portal lymphadenectomy. Negative microscopic margins of resection (R0) were achieved in all patients. Table 2 lists postoperative morbidity and mortality by liver resection. Severe postoperative complications occurred in 8 of 22 (36%) patients. These included vocal cord paralysis (n 1), intraabdominal abscess and biloma requiring drainage (n 3), fascial dehiscence (n 2), deep venous thrombosis (n 1), and sepsis with multisystem organ failure resulting in death (n 1). In our small series, 5 of 11 (45%) of patients who underwent major hepatic resection suffered severe postoperative morbidity versus 3 of 11 (27%) patients who underwent minor hepatectomy (P.42). Severe complications were more often seen in patients who underwent bile duct excision (8 of 12 [67%] vs 1 of 10 [10%], P.05). For patients who underwent extended hepatic resection, median hospital stay was 9 days (4 to 30 days) versus 7 days (3 to 28 days) for patients who underwent minor hepatectomy (P.12). Median follow-up for all patients was 37 months. Kaplan-Meier curves for overall and recurrence free survival are displayed in Fig. 1. Actuarial 3-year overall and recurrence-free survival in our small series was 72% and 68%, respectively. Of the 11 patients who underwent major hepatic resection, 5 of 11 (45%) had no evidence of disease (NED), 1 of 11 (9%) was alive with disease, and 5 of 11 (45%) were dead of disease at last follow-up. All cases of first disease recurrence consisted of disseminated disease. For patients who underwent previous laparoscopic cholecystectomy, there were no significant differences in median overall or recurrence-free survival between patients who underwent extended compared with minor hepatic resections (Fig. 2). Patients with T3 tumors had shorter long-term survival than those with T2 disease (Fig. 3). Thirteen of 22 Table 2 Postoperative mortality and morbidity by hepatic resection type Liver resection n Severe complication Reoperation 4B/5 wedge resection/ bisegmentectomy 4B/5 wedge resection/ bisegmentectomy with BDE Extended right hepatectomy Extended right hepatectomy with BDE Total BDE bile duct excision. Mortality Fig. 1. Overall and recurrence-free survival after hepatic resection for all 22 patients with gallbladder cancer. (59%) of patients received adjuvant chemotherapy or radiotherapy. Administration of adjuvant therapy did not affect overall or recurrence-free survival. Table 3 lists stages and treatments for 5-year survivors after partial hepatectomy. All but 1 of these patients were treated with adjuvant therapy. Comments Extended hepatectomy may provide long-term oncologic survival in selected patients with gallbladder cancer by ensuring a negative margin of resection, which many investigators have shown is a key positive predictor of long-term survival [1,4,8 10]. Because radical cholecystectomy is often associated with a minimal margin at the base of the cystic plate (because of the relatively thin liver parenchyma interposed between the gallbladder and the main right or sectoral bile ducts), extended hepatic resection may be necessary to achieve negative margins, particularly for large cancers located in the infidibulum or in Hartmann s pouch or that extend into the triangle of Calot. This point is especially important for patients who (1) present for definitive surgical resection after previous simple cholecystectomy for acute cholecystitis, (2) who underwent previous open cholecystectomy, (3) who have a positive cystic duct margin after simple cholecystectomy, (4) who have known node-positive disease, and/or (5) who present with preoperative jaundice caused by biliary obstruction. In these patients, the triangle of Calot is often obliterated by tumor or scar, thus making it difficult to distinguish cancer from benign inflammatory tissue. Extended hepatic resection may be especially useful in these patients as a sure method to achieve an oncologically negative resection margin by staying outside the plane of previous surgery. Other groups have also recognized the potential of extended resection in patients with gallbladder cancer. Kondo et al [11] stated that extended right hepatectomy was necessary for curative resection in cases of hepatic hilum gallbladder carcinomas. Furthermore, Shiari et al [12] demonstrated that the extent of hepatic microscopic angiolymphatic portal tract invasion correlates with gross tumor depth. Therefore, a greater resection may be needed for thicker tumors to achieve microscopically negative margins. However, despite recent decreases in the incidence of complications after liver resection, several large studies have noted extended hepatectomy to be a predictor of postoperative morbidity and

4 358 S.K. Reddy et al. / The American Journal of Surgery 194 (2007) Fig. 2. Overall and recurrence-free survival by extent of resection for patients who underwent previous laparoscopic cholecystectomy. mortality [13-15]. Given this setting, we evaluated our series of hepatic resection for gallbladder cancer where extended hepatectomy was performed in patients suspected to have disease near the cystic plate. The lack of differences in postoperative mortality and median length of hospital stay between major and minor hepatectomy suggests that extensive hepatic resection can be done safely in patients with gallbladder cancer (Table 2). None of the patients who underwent major hepatectomy experienced postoperative mortality or required reoperation. Although this absence of postoperative mortality rate is likely due to small patient numbers, several other studies have reported low (10% to 30%) mortality rates (Table 4). Extended hepatectomy was associated with a higher frequency of severe postoperative complications than with minor resections in our study (45% vs 27%); however, small patient numbers precluded an adequate analysis of significance. Our morbidity rate is consistent with that found in other studies (Table 4). Common bile duct excision was associated with postoperative morbidity (67% vs 10%), a finding confirmed by others [3]. In this small series, extended hepatectomy achieved a negative resection margin in those patients with high likelihood of disease and/or inflammation near the cystic plate. Long-term survival after major hepatectomy in these selected patients was similar to those patients not likely to have cancer or inflammation near the cystic plate and who consequently underwent minor hepatectomy (Fig. 2). Extended hepatectomy is also associated with good long-term outcomes in patients with advanced primary (T3) and nodal disease. Five of eleven (45%) patients who underwent major resection were NED at last follow-up, and two of seven 5-year survivors underwent extended right hepatectomy (Table 3). The two 5-year survivors who underwent major hepatectomy were either afflicted with thick tumors (T3) or regional nodal disease, and all of these long-term survivors were treated with adjuvant chemoradiotherapy. This finding of long-term survivors after extensive hepatic resection is in agreement with several other reports (Table 4). As expected, patients with T2 tumors had longer overall survival than those with T3 cancers (Fig. 3). However, our 62-month overall and 51-month recurrence-free survival are greater than those reported by other investigators [1 6,8,16 19]. Several differences exist between our study and other reports that may portend a more favorable outcome in our series. Most patients in other studies had stage III or stage IV disease, whereas the majority of patients in our series who underwent major hepatic resection had stage II disease. All of our patients underwent microscopically negative margin of resection (which increases the likelihood of long-term survival) compared with most studies in which only a subset of patients underwent curative resection. Also, many other series included patients who underwent concomitant other major procedures, such as pancreaticoduodenectomy or major vein reconstruction. PVE is performed before extended hepatectomy to induce hypertrophy of the future liver remnant (and by correlation an increase in synthetic function) to minimize postoperative complications caused by hepatic insufficiency. Four of 11 patients in our series received PVE before undergoing extended right hepatectomy due to a small liver remnant as estimated by CAT scan. Although all 4 patients experienced posthepatectomy complications, none of these complications were caused by hepatic insufficiency, and there was no postoperative mortality. The most extensive experience with PVE before extended hepatectomy for gall- Fig. 3. Overall and recurrence-free survival by tumor stage.

5 S.K. Reddy et al. / The American Journal of Surgery 194 (2007) Table 3 Tumor characteristics and treatment of 5-year survivors after partial hepatectomy* Stage Liver resection BDE Time since resection (mo) Adjuvant therapy Status T 2 N 0 4B/5 wedge N 122 Y NED T 2 N 0 4B/5 bisegmentectomy N 76 N NED T 3 N 0 Extended right hepatectomy N 71 Y NED T 2 N 0 4B/5 wedge Y 62 Y DOD T 3 N 0 4B/5 bisegmentectomy Y 62 Y DOD T 2 N 1 4B/5 wedge Y 68 Y NED T 2 N 1 Extended right hepatectomy Y 67 Y NED Disease status reported as of last follow-up. BDE bile duct excision; DOD dead of disease; NED no evidence of disease. * Months since hepatic resection was calculated from date of death or date of analysis for living patients. bladder cancer was reported by Nagino et al [19]. In this study, PVE was performed if the size of the future liver remnant was expected to be 40% of the total liver volume, a more liberal guideline for noncirrhotic patients than we and others have used [20,21]. Sixty-one patients with gallbladder cancer underwent major hepatic resection with bile duct excision and hepaticojejunostomy after PVE. Postoperative mortality was 18%, and poor functional reserve of the future liver remnant predicted mortality. In these patients with advanced disease who often underwent concomitant other major procedures, the 3-year and 5-year survival rates were 25.3% and 17.1%, respectively. In addition to improving postoperative liver function, another advantage to PVE is that it may spare patients with aggressive disease an unnecessary liver resection because disease progression would be noted on the CAT scan after PVE but before planned partial hepatectomy. We observed this aggressive tumor biology in 3 of 7 patients not treated with PVE who experienced disease recurrence within 6 months after extended hepatectomy. Although we did not see any difference in tumor burden after PVE by CAT scan, Nagino et al [19] noted that the incidence of unresectability after PVE caused by tumor progression was 32.2%. What is not clear, however, is the role PVE itself plays in leading to this unresectability by promoting tumor growth through stimulating cell division of not only benign hepatocytes but of tumor cells as well. More studies on the use of PVE specifically with gallbladder cancer need to be performed to shed light on this important issue. We concur with other investigators [20,22] that PVE should be performed when the left lateral section is 25% of liver volume (in noncirrhotic livers) or 40% of liver volume (in cases of cirrhosis Table 4 Review of series with 10 extended hepatic resections for gallbladder cancer Study Year n Mortality (%) Morbidity (%) Survival Comments Ogura et al [16] Major hepatic resection associated with greater mortality than smaller resections Matsumoto et al [18] Mean mo for ERH BDE curative resections 6 of 10 curative resections; 1 stage III patient and 9 stage IV patients; Bloechle et al [8] y survivors: 3 5-y survivors: 0 9 of 10 curative resections; 4 stage III and 6 stage IV patients; type of resection did not impact survival Bartlett et al [3] Median hospital stay was 21 days Tsukada et al [4] Fong et al [5] Lobectomy or greater resection predicted mortality and morbidity; obstructive jaundice predicted mortality Endo et al [17] y survivors: 2 Lobectomy positively predicted survival with hepatoduodenal ligament invasion Kondo et al [2] y survivors: 7 5-y survivors: 4 All with stage III/IV disease; hepatic failure most common cause of death; obstructive jaundice predicted mortality Kondo et al [11] % 3- and 5-y survivors 18% 3- and 5-y survivors All curative resections; survival summarized for bed and hilum and hepatic hilum type cancers; 1 stage III and 45 stage IV patients Kondo et al [6] ERH in a cholestatic liver predicted mortality, resection type did not predict survival Nagino et al [19] y survivors: 10 5-y survivors: 5 All received PVE, all curative resections, poor hepatic function of future liver remnant predicted mortality This study y survivors: 3 All curative resections Note. Data specified are for lobectomy or extended hepatectomy only. Mortality and morbidity refer to postoperative events, and survival refers to long-term outcome. BDE bile duct excision; ERH extended right hepatectomy; PVE portal vein embolization.

6 360 S.K. Reddy et al. / The American Journal of Surgery 194 (2007) or cholestasis) by CAT scan. However, there are presently no clear data from large retrospective case series or prospective randomized trials to support these guidelines. PVE should not be considered in patients with tumor invasion into the portal vein because benefits to the procedure are likely to be minimal. Whether the extent of resection itself influences longterm survival is not well defined because larger studies reveal conflicting results [6,8,17]. In our smaller series, the extent of hepatic resection did not influence long-term outcome in patients who underwent previous laparoscopic cholecystectomy (Fig. 2). We believe that extended hepatectomy can be used to ensure a margin-negative resection in those patients likely to have inflammation or tumor near the cystic plate. PVE should be used to make this option available to patients with small future liver remnants. Patient contraindications to extended hepatectomy should consist of characteristics that we and others have shown to predict morbidity or mortality in large institutional series, including increased creatinine, thrombocytopenia, jaundice, old age, severe chronic obstructive pulmonary disease, presence of preoperative infection, and high American Society of Anesthesiology and Child-Turcotte-Pugh scores [13 15,23]. The role of adjuvant chemotherapy and radiotherapy in the treatment of gallbladder cancer is controversial. Although the use of adjuvant therapy did not predict overall or recurrence-free survival, six of seven 5-year survivors received adjuvant therapy. This suggests that adjuvant therapy may improve long-term outcome in patients who undergo liver resection for gallbladder cancer. This is in agreement with our previous report, which revealed a median overall survival of 3.7 years, 5-year overall survival of 51%, and 5-year recurrence-free survival of 39% among 13 patients who underwent radical cholecystectomy [24]. In addition to external-beam radiotherapy, most of these patients also received 5-fluorouracil. Kresl et al [22] also demonstrated benefit from adjuvant external beam radiotherapy and 5-fluorouracil with 5-year survival of 33% and median survival of 2.6 years. A key justification for the use of adjuvant radiotherapy in particular is improvement of local and regional disease control. These studies have reported a 5-year local and regional control rates of 64% [24] and 73% [22], respectively. In our small case series, which only included patients who underwent hepatic resection, 3-year local control was 75% and 5-year local control was 66% for adjuvant chemotherapy and radiotherapy. However, in patients not given adjuvant therapy, all disease recurrences (3 of 9 patients) were systemic, thus questioning the role of local and regional therapies. This highlights the need for larger retrospective studies and prospective clinical trials that evaluate the efficacy of adjuvant therapy for gallbladder cancer. There are several limitations to our study. The retrospective nature, along with the absence of a true control group (patients likely to have disease near the cystic plate who underwent minor hepatectomy) hampered our ability to make definitive conclusions about the benefits of extended hepatic resection for gallbladder cancer. The relative small number of patients in our series increased the possibility that we did not detect an outcome difference between patients who underwent major and minor hepatic resections (type II error). Although postoperative morbidity, mortality, and long-term survival in this study were similar to those of larger series, small study size, frequent use of adjuvant chemotherapy (which is not the standard of care), and few cases of preoperative jaundice may hinder comparison of these results with those of most large centers. We conclude that extended hepatic resection may be useful in providing negative resection margins for patients that likely to have inflammation or tumor near the cystic plate. Although we cannot make definitive conclusions about whether extended hepatectomy portends a better oncologic outcome than standard radical cholecystectomy, data from our small series in conjunction with those of other reports show that long-term survival is possible in patients with thick primary tumors and/or regional nodal disease. Because of increased risk of postoperative morbidity, we believe that extended hepatectomy should not be routinely considered for all patients with gallbladder cancer nor in frail elderly patients with major medical comorbidity. Extended resection may require preoperative PVE in some patients, which may play a role in enhancing tumor growth. Given the paramount importance of a margin negative resection, extended hepatectomy should be considered in selected patients with gallbladder cancer. References [1] Dixon E, Vollmer CM, Sahajpal A, et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer. Ann Surg 2005;241: [2] Kondo S, Nimura Y, Hayakawa N, et al. Extensive surgery for carcinoma of the gallbladder. Br J Surg 2002;89: [3] Bartlett DL, Fong Y, Fortner JG, et al. Long-term results after resection for gallbladder cancer: implications for staging and management. Ann Surg 1996;224: [4] Tsukada K, Hatakaeyama K, Kurosaki I, et al. 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