Hepatectomy Before Primary Tumor Resection as Preferred Approach for Synchronous Liver Metastases from Rectal Cancer.

BACKGROUND: For patients with synchronous liver metastases (LM) from rectal cancer, a consensus on surgical sequencing is lacking. We compared outcomes between the reverse (hepatectomy first), classic (primary tumor resection first), and combined (simultaneous hepatectomy and primary tumor resection) approaches. METHODS: A prospectively maintained database was queried for patients with rectal cancer LM diagnosed before primary tumor resection who underwent hepatectomy for LM from January 2004 to April 2021. Clinicopathological factors and survival were compared between the three approaches. RESULTS: Among 274 patients, 141 (51%) underwent the reverse approach; 73 (27%), the classic approach; and 60 (22%), the combined approach. Higher carcinoembryonic antigen level at LM diagnosis and higher number of LM were associated with the reverse approach. Combined approach patients had smaller tumors and underwent less complex hepatectomies. More than eight cycles of pre-hepatectomy chemotherapy and maximum diameter of LM > 5 cm were independently associated with worse overall survival (OS) (p = 0.002 and 0.027, respectively). Although 35% of reverse-approach patients did not undergo primary tumor resection, OS did not differ between groups. Additionally, 82% of incomplete reverse-approach patients ultimately did not require diversion during follow-up. RAS/TP53 co-mutation was independently associated with lack of primary resection with the reverse approach (odds ratio: 0.16, 95% CI 0.038-0.64, p = 0.010). CONCLUSIONS: The reverse approach results in survival similar to that of combined and classic approaches and may obviate primary rectal tumor resections and diversions. RAS/TP53 co-mutation is associated with a lower rate of completion of the reverse approach.

Neoadjuvant chemotherapy for high-risk intrahepatic cholangiocarcinoma - does pathologic response mean better outcomes?

BACKGROUND: The role of neoadjuvant chemotherapy (NAC) in the management of intrahepatic cholangiocarcinoma (ICC) remains unknown. We sought to evaluate our experience treating high-risk ICC with NAC and to determine the prognostic significance of pathologic response. METHODS: Patients with ICC treated with NAC and surgery were analyzed using a prospectively maintained database. Pathologic response was graded by a blinded pathologist. Clinicopathologic/treatment variables were evaluated for associations with survival. RESULTS: Among 45 patients who received NAC followed by hepatectomy for high-risk ICC, 32(71%) were considered stage III, and 6(13%) were considered stage IV at time of diagnosis. Major response was identified in 39% of cases, including 2 with pathologic complete response. Patients with major response had a longer median NAC duration than patients with minor response (6 vs 4cycles, P=0.02). Regimen (gemcitabine/cisplatin vs gemcitabine/cisplatin/nab-paclitaxel) was not associated with response rate. Median recurrence-free (RFS) and overall survival (OS) were 11 and 45 months. Pathologic response was not associated with improved survival. CONCLUSION: Pathologic response to NAC was not associated with survival in this highly selected cohort. Nonetheless, the extended OS experienced by these high-risk patients is encouraging and suggests that NAC may help select patients who stand to benefit from aggressive resection.

Robot-assisted liver resection: the real benefit so far.

BACKGROUND: Minimally invasive liver resection is associated with lower perioperative morbidity and shorter hospital stay. However, the added benefit of the robotic platform over conventional laparoscopy is a matter of ongoing investigation. PURPOSE: The purpose of this narrative review is to provide an up-to-date and balanced evaluation of the benefits and shortcomings of robotic liver surgery for the modern hepatobiliary surgeon. CONCLUSIONS: Advantages of a robotic approach to liver resection include a shortened learning curve, the ability to complete more extensive or complex minimally invasive operations, and integrated fluorescence guidance. However, the robotic platform remains limited by a paucity of parenchymal transection devices, complete lack of haptic feedback, and added operating time associated with docking and instrument exchange. Like laparoscopic hepatectomy, robotic hepatectomy may provide patients with more rapid recovery and a shorter hospital stay, which can help offset the substantial costs of robot acquisition and maintenance. The oncologic outcomes of robotic hepatectomy appear to be equivalent to laparoscopic and open hepatectomy for appropriately selected patients.

Gallbladder squamous cell carcinoma: An analysis of 1084 cases from the National Cancer Database.

BACKGROUND/OBJECTIVES: Gallbladder squamous cell carcinoma (SCC) is an uncommon malignancy whose rarity has made it particularly challenging to study. We utilized a national database to shed light on the clinicopathologic characteristics, management patterns, and survival associated with these tumors. METHODS: Patients with gallbladder SCC were identified in the National Cancer Database. Clinicopathologic and treatment characteristics were recorded and compared with adenocarcinoma for context. Univariate and multivariable survival analyses were completed for patients who underwent resection. RESULTS: Overall, 1084 patients with SCC and 23 958 patients with adenocarcinoma were identified. Compared with those with adenocarcinoma, patients with SCC had higher grade tumors (P < .001) and were diagnosed at a later stage (P < .001). Patients with SCC were more likely to undergo radical cholecystectomy (17% vs 9%; P < .001), but had a higher rate of margin positivity (36% vs 29%; P < .001). SCC histology was associated with worse survival compared with adenocarcinoma, even after adjusting for R0 resections (13 vs 29 months; P < .001). On multivariable analysis, SCC histology was independently associated with abbreviated survival (P = .003). CONCLUSIONS: Gallbladder SCCs are aggressive cancers that often present at an advanced stage. Complete surgical extirpation should be pursued when feasible. However, prognosis is worse than that of adenocarcinoma, even after R0 resection.

Stage and disease-free interval help select patients for surgical management of locally recurrent and metastatic adrenocortical carcinoma.

BACKGROUND AND OBJECTIVES: Chemotherapeutic options for patients with recurrent/metastatic adrenocortical carcinoma (ACC) are limited, leading to consideration for surgical management. We sought to determine characteristics associated with an unequivocal survival benefit amongst patients undergoing re-resection or metastasectomy. METHODS: Patients who underwent surgery for recurrent/metastatic ACC were identified and stratified into two groups: those with postoperative survival comparable with what has been reported with chemotherapy alone (<12 months) and those surviving twice that duration (>24 months). Those who survived between 12 and 24 months were excluded, as the objective was to characterize patients who most distinctly benefited from resection. Clinicopathologic and treatment variables were evaluated for associations with survival. RESULTS: Forty-three patients survived more than 24 months and 15 patients died less than 12 months after reoperation. Tumor stage (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.45-0.96) and disease-free interval (DFI; OR, 3.23; 95% CI, 1.68-6.22) were associated with prolonged survival. Tumor size, hormonal status, resection margin, and treatment with chemotherapy, radiation, and mitotane were not associated with prolonged survival. Patients who survived more than 24 months underwent more procedures for subsequent recurrences (median 4 vs 2; P < .001). CONCLUSION: Stage and DFI can help select optimal candidates for resection of recurrent/metastatic ACC. Patients selected for surgical management should be informed of the likelihood of requiring multiple interventions.

Tumor grade may be used to select patients with multifocal hepatocellular carcinoma for resection.

BACKGROUND: While resection is a recommended treatment for patients with stage 1 hepatocellular carcinoma (HCC), it remains controversial for multifocal disease. We sought to identify patients with multifocal HCC with survival after resection similar to patients with clinical stage 1 HCC. METHODS: The National Cancer Database was queried to identify patients that underwent resection for HCC. RESULTS: In this study, 2990 patients with a single tumor, and 1087 patients with multifocal disease confined to one lobe underwent resection. In the multifocal cohort, patients with clinical stage 3 (HR 1.54, CI 1.31-1.81, p < 0.0001) or 4 (HR 2.27, CI 1.57-3.29, p < 0.0001) disease, and those with moderately-differentiated (HR 1.32, CI 1.06-1.64, p = 0.012) or poorly differentiated/undifferentiated tumors (HR 1.53, CI 1.20-1.95, p = 0.0006) were associated with worse overall survival (OS). There was no difference in OS between patients with well-differentiated clinical stage 2 multifocal HCC and those with all grades of clinical stage 1 HCC (median of 84.8 (CI 66.3-107.2) vs 76.2 months (CI 71.2-81.3), respectively, p = 0.356). CONCLUSIONS: Patients with well-differentiated, clinical stage 2 multifocal HCC confined to one lobe experience similar OS following hepatic resection to patients with clinical stage 1 disease. These findings may impact the management of select patients with multifocal HCC.

Resection and chemotherapy is the optimal treatment approach for patients with clinically node positive intrahepatic cholangiocarcinoma.

BACKGROUND: Clinically lymph node positive (cLNP) intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, without clear management guidelines for the practicing clinician. We sought to evaluate current practice patterns for cLNP ICC, including associations with survival. METHODS: The National Cancer Database was queried for patients with cLNP ICC, without extrahepatic metastases. RESULTS: We identified 1023 patients with cLNP ICC, 77%% (n = 784) of whom received chemotherapy alone. Resection was undertaken in 23% (n = 239) of patients and was most commonly utilized in combination with chemotherapy (n = 150). Median survival for all patients was 13.6 months. Patients undergoing resection in combination with chemotherapy were associated with an improved survival (22.5 months) as compared to those patients receiving chemotherapy alone (11.9 months) or resection alone (12.4 months) (p < 0.01). Finally, we compared the survival of patients with cLNP ICC with that of patients with pathologically proved lymph node positive (pLNP) ICC, all of whom were treated with resection with chemotherapy, and found no difference in survival (22.5 months-19.3 months, p = 0.99, respectively). CONCLUSIONS: While the decision to pursue resection for ICC is multifactorial and patient specific, the presence of clinically positive LNs should not represent a contraindication.

Disease-free interval and tumor functional status can be used to select patients for resection/ablation of liver metastases from adrenocortical carcinoma: insights from a multi-institutional study.

BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive malignancy that frequently metastasizes to the liver. Given the limitations of systemic therapy in this setting, we sought to determine characteristics associated with a two-fold increase in survival with resection/ablation compared to that reported with chemotherapy alone (∼12 months). METHODS: Patients who underwent resection/ablation at our institutions for ACC liver metastases were identified. Those who survived 12-24 months after metastasectomy were excluded, as the aim was to characterize patients who most clearly benefited from these procedures. Clinicopathologic and treatment characteristics were assessed for associations with survival. RESULTS: Sixty-two patients met inclusion criteria, of whom 44 survived >24 months and 18 survived <12 months. Patients with extended survival were less likely to have functioning tumors (p = 0.047), had fewer liver metastases (p = 0.047), and a longer disease-free interval (DFI) (median 17.6 vs 2.3 months, p < 0.0001). On multivariable analysis, DFI (OR = 1.33, 95% CI = 1.12-1.58) and non-functioning tumor (OR = 0.13, 95% CI = 0.13-0.56) were independently associated with prolonged survival. CONCLUSION: Metastasectomy/ablation should be considered for patients with ACC liver metastases. DFI and tumor functional status may be useful in selecting optimal candidates for these procedures.

Primary Gallbladder Neuroendocrine Tumors: Insights into a Rare Histology Using a Large National Database.

BACKGROUND: Primary gallbladder neuroendocrine tumors (NETs) are rare, poorly understood cancers infrequently encountered at even the largest of tertiary referral centers. We therefore sought to identify a large cohort of patients with gallbladder NETs using a national database, with the aim of defining treatment modalities employed and survival associated with these uncommon malignancies. METHODS: Patients with primary gallbladder NETs were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. A univariate log-rank survival analysis was completed for patients who underwent resection. Parameters found to be significant were entered into a multivariate accelerated failure time analysis. For context, survival comparisons were included for patients who underwent resections for NETs at any gastrointestinal site and for gallbladder adenocarcinoma. RESULTS: Overall, 754 patients with gallbladder NETs were identified. Patients were predominantly female (n = 518, 69%), White (n = 503, 67%), presented with stage IV disease (n = 295, 39%) and had high-grade lesions (n = 312, 41%). The majority underwent resection (n = 480, 64%), primarily simple cholecystectomy (n = 431, 90%), whereas a minority received multimodal therapy (n = 145, 21%). Among patients who underwent resection, older age (p = 0.001), large cell histology (p = 0.012), and positive margins (p = 0.030) were independently associated with worse overall survival. Patients with gallbladder NETs had improved survival relative to those with gallbladder adenocarcinoma (p = 0.001), but significantly worse survival than patients with NETs from other gastrointestinal sites (p < 0.001). CONCLUSIONS: Primary gallbladder NETs are aggressive lesions that carry a worse prognosis than NETs of other gastrointestinal sites. Older age, positive margins, and large cell histology are associated with abbreviated survival after resection.

Laparoscopic Approach to Intrahepatic Cholangiocarcinoma is Associated with an Exacerbation of Inadequate Nodal Staging.

INTRODUCTION: Laparoscopic approach to liver resection is feasible and safe, though its utilization with intrahepatic cholangiocarcinoma (ICC) remains poorly documented. We sought to evaluate the use laparoscopy for ICC, and to examine adherence to oncologic standards. METHODS: The National Cancer Database was queried for patients who underwent resection for ICC. Patients were stratified by laparoscopic (LLR) versus open liver resection (OLR). Clinicopathologic parameters and hospital volumes were recorded. RESULTS: In total, 2309 patients with ICC underwent hepatic resection (1997 OLR, 312 LLR) between 2010 and 2015. LLR increased from 12 to 16% during the study period and was utilized more commonly than OLR for wedge and segmental resections (56% vs. 33%, p < 0.001). Nodal evaluation was performed in 58% of all patients with ICC and was significantly more common in patients undergoing OLR (61%, n = 1210) versus LLR (39%, n = 120), p < 0.001. Of the 120 patients undergoing LLR with any nodal evaluation, 31% (n = 37) had a single node evaluated. Patients who underwent LLR were less likely to have ≥ 6 lymph nodes evaluated compared with those who underwent OLR (9% vs. 15%, respectively, p < 0.001). CONCLUSIONS: The use of laparoscopy for ICC is associated with an exacerbation of inadequate nodal evaluation compared with open resections.

A Survey of the Complex General Surgical Oncology Fellowship Programs Regarding Applicant Selection and Rank.

BACKGROUND: There is significant demand for training in Complex General Surgical Oncology (CGSO) fellowships. Previous work has explored objective quantitative metrics of applicants that matriculated to CGSO fellowships; however, ambiguity remains concerning academic benchmarks and qualitative factors that impact matriculation. STUDY DESIGN: A web-based survey was sent to each ACGME/SSO-approved CGSO fellowship training program. The survey was comprised of 24 questions in various forms, including dichotomous, ranked, and five-point Likert scale questions. RESULTS: Twenty-nine of 30 program directors (97%) submitted complete survey responses, representing 64 of the 65 CGSO fellowship positions (99%) currently offered. Programs received a mean of 73 applications per cycle (range 50-125) and granted a mean of 26 interviews (range 2-45). Seventy-two percent of programs had an established benchmark for ABSITE score percentile before offering a candidate an interview, with 62% of those programs setting that benchmark above the 50th percentile. The majority of programs also had established benchmarks for quantity of first author publications (mean: 2.3) and all publications of any authorship (mean: 4.4). An applicant's interview was ranked as the most important factor in determining inclusion on the program's rank list. The ability to work as part of a team, interpersonal interaction/communication abilities, and operative skills were rated as most important applicant characteristics, whereas an applicant's personal statement was ranked as least important. CONCLUSIONS: After established academic benchmarks have been met, a multitude of factors influences ranking of applicants to the CGSO fellowship, most of which are assessed at the interview.

MicroRNA-210 May Be a Preoperative Biomarker of Malignant Pheochromocytomas and Paragangliomas.

BACKGROUND: Currently, no reliable predictive clinical or laboratory tests exist that can accurately distinguish between benign and malignant pheochromocytomas or paragangliomas (PPGLs). The aim of this study was to investigate if serum microRNA-210 (miR-210) levels could be a marker of malignancy in patients with PPGLs. METHODS: Preoperative serum from patients with PPGLs was collected on the day of surgery. Clinical demographics, germline mutation status, primary tumor size, postoperative biochemical response, and the development of malignant disease were prospectively collected. Total microRNA was extracted from preoperative serum samples, and miR-210 levels were measured by quantitative real-time reverse transcription-polymerase chain reaction and normalized to miR-16. Prognostic variables were compared using univariable and multivariable analyses. RESULTS: Of the 35 patients, 10 (29%) were diagnosed with malignant PPGLs and 25 patients (71%) were diagnosed with benign PPGLs (median follow-up 72.5 mo). Sixty-nine percent of patients had a pheochromocytoma (n = 24/35) compared with 31% of patients with paraganglioma (n = 11/35). The most common germline mutation was succinate dehydrogenase complex subunit B (SDHB) (n = 10). On univariable analysis, lower serum miR-210 expression level (2.3 ± 0.5 versus 3.1 ± 1.2, P = 0.013) and larger primary tumor size (6.7 ± 5.0 cm versus 4.1 ± 2.3 cm, P = 0.043) were significantly associated with malignant disease. No significant prognostic variables were found on multivariable analysis. CONCLUSIONS: In this pilot study, low serum miR-210 expression levels and large primary tumors were identified to be markers of PPGL malignancy on univariable analysis. Given the initial encouraging results in a small cohort, further investigation is warranted to determine if serum miR-210 levels are prognostic.

Postbiliary drainage rates of cholangitis are impacted by procedural technique for patients with supra-ampullary cholangiocarcinoma: A SEER-Medicare analysis.

BACKGROUND: The optimal approach to biliary drainage for patients with supra-ampullary cholangiocarcinoma remains undetermined. Violation of sphincter of Oddi results in bacterial colonization of bile ducts and may increase postdrainage infectious complications. We sought to determine if rates of cholangitis are affected by the type of drainage procedure. METHODS: We examined the Surveillance, Epidemiology, and End Results-Medicare linked database from 1991 to 2013 for cholangiocarcinoma. Biliary drainage procedures were categorized as sphincter of Oddi violating (SOV) or sphincter of Oddi preserving (SOP). Patients were stratified by resection. RESULTS: A total of 1914 patients were included in the final analysis. A total of 1264 patients did not undergo a postdrainage resection (SOP 83, SOV 1181) while 650 did undergo a postdrainage resection (SOP 26, SOV 624). For those patients not undergoing a postdrainage resection, the rate of cholangitis 90 days after an SOP procedure was 19% compared with 34% in the SOV cohort (P = 0.007). For those patients undergoing a postdrainage resection, the rate of cholangitis 90 days after an SOP procedure was less than 42.3% compared with 30% in the SOV cohort (P = 0.66). CONCLUSION: For patients with supra-ampullary cholangiocarcinoma that did not undergo resection, biliary drainage procedures that violated the sphincter of Oddi were associated with increased rates of cholangitis.

Practice patterns of VTE chemoprophylaxis after discharge following hepatic and pancreatic resections for cancer: A survey of hepatopancreatobiliary surgeons.

Patients with hepatopancreatobiliary (HPB) malignancies undergoing resection are prone to venous thromboembolism (VTE), and current guidelines recommend up to 28 days of chemoprophylaxis after major surgery. We sought to determine the practice patterns among HPB surgeons for use of chemoprophylaxis after discharge. A survey on VTE chemoprophylaxis after oncologic HPB operations was distributed to attending surgeons at the 18 HPB fellowship training programs in the United States and Canada. Of the HPB surgeons surveyed, 44 (44%) responded. VTE prophylaxis is used by 93% of respondants in the inpatient postoperative setting. Chemoprophylaxis after discharge for pancreaticoduodenenctomy and distal pancreatectomy is utilized by 45% and 39% of respondants, respectively. Of those who prescribe chemoprophylaxis after discharge, 79% and 88% prescribe it for the recommended 28 days after pancreaticoduodenectomy and distal pancreatectomy, respectively. Chemoprophylaxis after discharge for major and minor hepatectomy is utilized by 39% and 26% of respondents, respectively. Of those who prescribe chemoprophylaxis after discharge, 67% and 55% provide it for the recommended 28 days after major and minor hepatectomy, respectively. Despite documented prolonged postoperative thrombogenic risk, the use of chemoprophylaxis following discharge after pancreatic and liver resections for cancer was moderate among surveyed HPB surgeons.

Tumor grade and sex should influence the utilization of portal lymphadenectomy for early stage intrahepatic cholangiocarcinoma.

BACKGROUND: Portal lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) is encouraged for staging purposes, though it is under-utilized for clinically early-stage tumors. We sought to determine if any factor knowable prior to resection influences rates of portal lymph node metastases. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program (1973-2014) database was queried to identify patients with T1/T2 ICC undergoing resection. Patients were stratified by lymph node (LN) status. Patients deemed LN negative required examination of six or more LNs (AJCC guidelines). RESULTS: One-hundred and fifty-two patients were included in the analysis (LN negative: 38, LN positive: 114). Patients with LN negative cancers experienced prolonged overall survival as compared to patients with positive LNs (median 77 months vs 19 months, respectively p < 0.001). Twelve patients had well-differentiated tumors (G1), 92 patients had moderately-differentiated tumors (G2) and 58 patients had poorly-differentiated tumors (G3). Tumor grade (OR 3.9, CI 1.1-13.7, p = 0.031) and male sex (OR 2.6, CI 1.1-6.1, p = 0.022) were associated with positive LNs on multivariable logistic regression analysis. CONCLUSION: Intermediate/High grade and male sex are associated with high rates of lymph node metastasis for patients with early-stage ICC, which portends abbreviated overall survival.

An Examination of Applicants and Factors Associated with Matriculation to Complex General Surgical Oncology Fellowship Training Programs.

BACKGROUND: The demand for training in complex general surgical oncology (CGSO) fellowships currently exceeds the number of positions offered; however, there are scarce data defining the applicant pool or characteristics associated with successful matriculation. Our study described the applicant population and to determine factors associated with acceptance into the fellowship. STUDY DESIGN: Data were extracted from the Electronic Residency Application System for applicants in 2015 and 2016 and stratified based on matriculation status. Applicant demographics, including medical education, residency, and research achievements, were analyzed. Academic productivity was quantified using the number of peer-reviewed publications as well as the journal with the highest impact factor in which an applicant's work was published. RESULTS: Data were gathered on a total of 283 applicants, of which 105 matriculated. The overall population was primarily male (63.2%), Caucasian (40.6%), educated at a U.S. allopathic medical school (53.4%), and trained at a university-based General Surgery residency (55.5%). Education at a U.S. allopathic school (OR = 5.63, p < 0.0001), university-based classification of the applicant's surgical residency (OR = 4.20, p < 0.0001), and a residency affiliation with a CGSO fellowship (OR = 2.61, p = 0.004) or National Cancer Institute designated Comprehensive Cancer Center (OR = 3.16, p < 0.001) were found to be associated with matriculation. Matriculants published a higher number of manuscripts than nonmatriculants (median of 10 vs. 4.5, p < 0.0001) and more frequently achieved publication in journals with higher impact factors (p < 0.0001). CONCLUSIONS: This study represents the first objective description of the CGSO fellowship applicant pool. Applicants' medical school, residency, and research data points correlated with successful matriculation.

Single-site robotic cholecystectomy and robotics training: should we start in the junior years?

BACKGROUND: It has become increasingly important to expose surgical residents to robotic surgery as its applications continue to expand. Single-site robotic cholecystectomy (SSRC) is an excellent introductory case to robotics. Resident involvement in SSRC is known to be feasible. Here, we sought to determine whether it is safe to introduce SSRC to junior residents. MATERIALS AND METHODS: A total of 98 SSRC cases were performed by general surgery residents between August 2015 and August 2016. Cases were divided into groups based on resident level: second- and third-years (juniors) versus fourth- and fifth-years (seniors). Patient age, gender, race, body mass index, and comorbidities were recorded. The number of prior laparoscopic cholecystectomies completed by participating residents was noted. Outcomes including operative time, console time, rate of conversion to open cholecystectomy, and complication rate were compared between groups. RESULTS: Juniors performed 54 SSRC cases, whereas seniors performed 44. There were no significant differences in patient age, gender, race, body mass index, or comorbidities between the two groups. Juniors had less experience with laparoscopic cholecystectomy. There was no significant difference in mean operative time (92.7 min versus 98.0 min, P = 0.254), console time (48.7 min versus 50.8 min, P = 0.639), or complication rate (3.7% versus 2.3%, P = 0.68) between juniors and seniors. CONCLUSIONS: SSRC is an excellent way to introduce general surgery residents to robotics. This study shows that with attending supervision, SSRC is feasible and safe for both junior and senior residents with very low complication rates and no adverse effect on operative time.