IMMUNOTHERAPY FOR ADVANCED HEPATOCELLULAR CARCINOMA, A SINGLE CENTER EXPERIENCE.

Background

Long-term survival in patients with localized pancreatic adenocarcinoma (PDAC) or ampullary adenocarcinoma (AA) who undergo resection is rare, even in lymph node (LN)-negative disease. We aimed to assess the frequency of occult metastases (OM) in patients with resected PDAC or AA discovered with a detailed pathologic examination technique on LNs previously considered negative with conventional analysis. We also examined the association between OM and overall survival (OS).

Methods

Patients with LN-negative disease on conventional pathologic analysis following resection of PDAC or AA from 2010 to 2020 were identified from our institutional database, and those with available tissue for re-analysis were included. LNs were selected for re-examination based on proximity to the tumor and size. Original hematoxylin & eosin slides, three 4-micron-thick sections from deeper levels, and one pan-cytokeratin (AE1/AE3/PCK26) immunostain were examined for each block. The primary outcome was the frequency of OM. The secondary outcome was OS.

Results

A total of 598 LNs from 74 LN-negative patients (PDAC=71; AA=3) were re-examined in detail. A total of 49 patients (66.2%) underwent pancreatoduodenectomy, 17 (23.0%) underwent distal pancreatectomy/splenectomy, and 7 (10.8%) underwent total pancreatectomy. The median LN yield was 19. Sixteen patients (21.6%) had positive surgical margins, 18 (24.3%) had lymphovascular invasion, and 47 (63.5%) had perineural invasion. Twenty-six patients (35.1%) received neoadjuvant therapy and 35 (47.3%) received adjuvant chemotherapy.
On detailed LN analysis, 19 patients (25.7%) had OM. Of these, 9 OM (47.4%) were found only with immunohistochemistry but not on hematoxylin & eosin staining. The number of positive lymph nodes ranged from 1-3. On multivariable analysis, no clinicodemographic or pathologic factors were associated with OM.
The proportion of OM was 10.5% for patients with operative LN yields of <10 LNs, 42.0% for 10-19 LNs, 37.0% for 20-29 LNs, and 10.5% for ≥30 LNs. On conventional pathologic analysis, 3 patients (15.8%) had stage IA disease, 9 patients (26.5%) had stage IB disease, and 7 patients (36.8%) had stage IIA disease, all upstaged to stage IIB on detailed LN analysis.
On survival analysis, patients with OM had an associated decrease in OS as compared to those without OM (median OS: 22.3 vs. 50.5 months; HR=3.86, 95% CI: 1.53-9.78; Figure).

Conclusions

There is a high discordance rate between conventional and detailed LN pathologic analysis in resected PDAC and AA. The presence of OM is associated with worse OS. The high rate of occult nodal disease may in part explain poor survival outcomes in patients with node-negative disease.

BACKGROUND:
Post-pancreatoduodenectomy patients at our institution are managed on risk-stratified pancreatectomy care pathways preoperatively determined by risk of clinically relevant postoperative pancreatic fistula (CR-POPF). We previously published cut-off ranges for drain fluid amylase on postoperative day (POD) 1 (DFA1) and POD 3 (DFA 3) to encourage timely drain removal. The aim of this study was to validate and recalibrate our cut-off values using a prospective cohort of patients managed immediately after implementing those DFA thresholds.

METHODS:
We performed a single-institution prospective cohort study of consecutive patients who underwent pancreatoduodenectomy from DFA1/DFA3 threshold implementation in February 2019 to April 2022. Ninety-day postoperative complications were prospectively graded and reported according to the ACCORDION system and International Study Group on Pancreatic Surgery definitions. Patient characteristics, perioperative details, and DFA1/DFA3 (measured in U/L) were compared between care pathways. Receiver Operating Characteristic (ROC) curve analysis was performed to determine optimal cut-off values based on preoperative risk stratification.

RESULTS:
In total, 267 patients underwent 228 (85%) open and 39 (15%) robotic procedures, with 173 (65%) patients stratified into low-risk and 94 (35%) into high-risk pathways. Seven (4%) low-risk patients and 21 (22%) high-risk patients developed CR-POPF. Of 147 patients with drains removed before/on POD3, only 1 (0.7%) developed CR-POPF in the prospective cohort recalibration. CR-POPF was excluded with 100% sensitivity if DFA1 <286 (area under curve, AUC=0.893, p=0.001) or DFA3 <97 (AUC=0.856, p=0.002) in low-risk patients. DFA1 <137 (AUC=0.786, p<0.001) or DFA3 <56 (AUC=0.819, p<0.001) were 100% sensitive in ruling out CR-POPF in high-risk patients. Our previous DFA1 cut-offs of 100 in low-risk patients and <26 in high-risk patients were 100% sensitive, while our DFA3 cut-offs of 300 (low-risk) and 200 (high-risk) had 57% and 91% sensitivity.

CONCLUSION:
Risk-stratified post-pancreatoduodenectomy DFA thresholds can effectively and safely guide early POD1/POD3 drain removal. Previously identified cut-off values appear overly restrictive for DFA1 and overly liberal for DFA3. As a learning health system, we further propose recalibrating our drain removal thresholds to DFA1 ≤300, DFA3 ≤100 in low-risk patients and DFA1 ≤100, DFA3 ≤50 in high-risk patients. This methodology can be implemented at other centers to develop institution-specific criteria for early drain removal.

Introduction: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. National guidelines recommend the consideration of use in patients with positive margins after resection, however, supporting evidence comes mainly from a phase II trial of 79 patients, SWOG S0809, which demonstrated that the use of adjuvant chemoradiation was well tolerated and resulted in an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer.

Methods: Using the National Cancer Database (NCDB), we selected patients from 2004-2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival using Cox proportional hazards model. We also examined overall survival in a subset of patients who received adjuvant chemo- and radiotherapy (CRT) using the Kaplan-Meier method and log rank test.

Results: Overall, 4,997 patients with gallbladder or extrahepatic adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected from the NCDB, 469 of whom received both adjuvant chemo- and radiotherapy. Of the CRT cohort, all patients received multi-agent chemotherapy, 211 (45.0%) had extrahepatic cholangiocarcinoma and 258 (55.0%) had gallbladder cancer, the majority were pT3 (n=281, 59.9%), pN1 (n=323, 68.9%), and had an R0 resection (n=387, 82.5%). Median overall survival in patients undergoing CRT was 36.9 months, and was not different between primary sites (p=0.841). Patients with a R1 margin had abbreviated overall survival compared to patients with an R0 resection (41.8 months vs 24.1 months, p<0.001). On multivariable cox regression analysis of all patients who underwent resection agnostic to adjuvant therapy, age, insurance status, Charlson-Deyo comorbidity index, T-stage, N-stage, lymphovascular invasion, margin status, chemo- and radiotherapy were all associated with overall survival. Adjuvant chemoradiation compared to chemotherapy alone showed an overall survival benefit for patients with either R0 (41.8 vs 30.8 months, p<0.001) or R1 (24.1 vs 20.2 months, p<0.001) resections.

Conclusion: Using a large national database, our data validates the findings of SWOG S0809 with a similar median overall survival in patients receiving chemoradiation. Patients receiving CRT had improved overall survival compared to patients receiving chemotherapy only after both R0 and R1 resections. These data further support the consideration of adjuvant multi-modal therapy in resected biliary cancers, regardless of margin status.

Background: For patients with synchronous liver metastases (LM) from rectal cancer, 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. Larger LM, BRAF mutation, and TP53 mutation were independently associated with worse overall survival (OS) (p = 0.001, 0.001 and 0.048, respectively). Although 35% of reverse-approach patients did not undergo primary tumor resection, OS did not differ between groups (Figure 1), and 82% of reverse-approach patients 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).
Conclusion: The reverse approach results in survival similar to that with the combined and classic approaches and may obviate primary rectal tumor resections and diversions that do not improve oncologic outcome but affect quality of life. RAS/TP53 co-mutation is associated with lower rate of completion of the reverse approach.

Introduction
Previous implementation of risk-stratified post-hepatectomy care pathways (RSPHPs) resulted in decreased length of stay (LOS) for open hepatectomy patients at our hospital. We hypothesized that RSPHPs would also result in decreased overall inpatient hospital costs in the 90-day global period.
Methods
Clinicopathologic data for consecutive patients undergoing open hepatectomy (1/2017-2/2022) were collected from a prospective database. Hospital billing data was acquired from the institution’s financial department, normalized to a constant dollar value for fiscal year 2022 and adjusted for inflation and annual institutional cost increase. Patients who underwent hepatectomy after implementation of RSPHPs (“POST,” 9/2019-2/2022) were compared to a historical cohort (“PRE,” 1/2017-8/2019). Postoperative inpatient costs, including those related to readmissions incurred within 90 days, were compared between the two groups. Costs were presented as a ratio (normalized to a value of 1) of the total cost of a service to the average cost of that service for the PRE cohort.
Results
Of the 673 patients undergoing hepatectomy, 45% (n=303) were part of the POST group. There were no differences between POST and PRE cohorts by age (median 55 vs. 58 years), major complications (9.6% vs 11.4%), or complexity of hepatectomy (47.9% vs. 44.6% Kawaguchi-Gayet Grade III, all p>0.05). Median estimated total hospital normalized cost of post-operative care for POST patients was 17.9% less than those of PRE patients (0.69 vs 0.84, p=0.001; Fig. 1). Cost decreases were primarily driven by a 25.8% reduction in sterile, non-sterile, and take-home supplies (0.66 vs 0.89, p=0.001). The second driver was a 21.3% decrease in pharmacy costs (0.59 vs 0.75, p=0.001). The median room and board cost ratio of the POST group decreased by 17.6% relative to the PRE group (0.56 vs 0.68, p=0.002) concurrently with a downward shift in the interquartile range of expected LOS (median 4 [IQR 3-5] vs 4 days [4-6], p=0.001). Similar cost reductions were seen when observing only cost ratios of index hospitalization, with total cost decreasing by 16.9% in the POST group (0.74 vs 0.89, p=0.001). There was no significant change in intensive care unit and stepdown unit use (1.70% vs 0.50%) or costs (0.91 vs 0.90, both p>0.05) between POST and PRE groups. Median cost ratios for readmissions (4.67 vs 6.08, p = 0.12) highlight the tremendous cost of readmissions in both cohorts, but stable readmission rates (9.5% vs 9.6%) prevented a rebound loss of savings from the index hospitalization.
Conclusion
Implementation of RSPHPs in 2019 was associated with decreased 90-day inpatient costs by standardizing care and reducing LOS without increasing readmissions. Continued iterative improvements in RSPHPs focusing on reducing major drivers of cost could lead to further cost-effective care following hepatectomy.

Background
The timing to surgery for acute cholecystitis (AC) remains variable, ranging anywhere from early (<7 days) to delayed surgery (>7 days). Accelerated surgery for AC may result in better outcomes by reducing patient exposure to inflammatory, hypercoagulable, and stress states. We undertook a pilot trial to determine the feasibility of providing accelerated care (i.e., surgery within 6 hours of diagnosis) compared to standard care among patients with calculus AC.

Methods
Adult patients with AC requiring surgery were randomized to receive accelerated surgery or standard care. The primary feasibility outcome included recruitment of 1 patient per site per month, ≥95% follow-up at 90 days, and determining timelines of accelerated surgery. The secondary outcome was a composite of major perioperative complications (all-cause mortality, reinterventions and reoperations, various intra- and post-operative complications, cardiovascular events, venous thromboembolism, bleeding) within 90 days of randomization. Other outcomes included individual components of the composite, length of hospital stay, readmissions, surgery duration, and feasibility of drawing preoperative point-of-care N-terminal-pro hormone BNP (NT-proBNP) in ≥90% of patients. Analysis included descriptive statistics and cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence interval (CI) for outcomes with time to event data.

Results
Sixty patients were randomly assigned to accelerated surgery (N=31) and standard care (N=29) across 4 Canadian hospitals. There was ≥1 patient recruited per site per month. All patients completed 90 day follow up. The median time and interquartile range (IQR) from diagnosis to surgery in the accelerated arm was 5.8 [4.4-11.1] hours versus 20.3 [6.8-26.8] hours in the standard care arm. A major perioperative complication occurred in 9/31 (29.0%) patients in the accelerated and 4/29 (13.8%) patients in the standard care arm (HR 2.42, 95% CI 0.74-7.91). The main contribution was from 5/31 (16.1%) versus 1/29 (3.4%) post-operative endoscopic retrograde cholangiopancreatography performed in the accelerated versus standard care arm, respectively (HR 5.11, 95% CI 0.60-43.9). Of note, 4/31 and 3/29 patients in the accelerated and standard care groups underwent intraoperative cholangiogram. Between both groups, there were no differences in surgery duration (mean (standard deviation): 86.8 (30.0) vs. 86.4(32.3) minutes), length of hospital stay (median [IQR]: 2.0 [1.0-3.0] vs. 2.0 [2.0-3.0] days), readmissions (2/31 vs. 4/29), or cardiovascular events (2/31 vs. 1/29). Preoperative NT-proBNP was drawn in 57/60 (95.0%) patients.

Conclusion
These results demonstrate the feasibility of a trial comparing accelerated and standard care among patients requiring surgery for AC and supports a definitive trial.

Introduction: Social risk factors impact the diagnosis, management and survival of patients with hepatocellular carcinoma (HCC). This is relevant as the incidence of HCC increases nationally, particularly among non-white, immigrant patients, yet receipt of treatment and overall outcomes for HCC continue to have disparities based on race, ethnicity, and socioeconomic status. We evaluated the relationship between social determinants of health and presentation, treatment and survival of patients with HCC at an urban, safety-net hospital.
Methods: A single institution retrospective chart review of patients with all stages of HCC from January 2009 through May 2019 was conducted. Demographic, disease, and treatment characteristics were obtained. Chi-square and Wilcoxon tests were used for categorical and continuous variables, respectively. Univariate analysis was used to evaluate stage at presentation, receipt of intervention (resection, ablation, TACE), receipt of systemic therapy and median overall survival. Survival between stage at diagnosis was compared using Kaplan-Meier methods.
Results: 388 patients with HCC were identified; median age was 61 years and 83.2% were male. Patients had an overall similar sociodemographic distribution for presentation of early versus late disease. However, commercial insurance status resulted in diagnosis at earlier stage (24.7% early stage vs 13.3% late stage; p=0.014) while safety-net/no insurance was a significant risk factor for advanced presentation at diagnosis (9.9% early stage vs 17.6% late stage; p=0.014). Higher level of education (high school and above) was associated with increased intervention for all stages of disease (70.1% vs no education/unknown 29.9%; p=0.048) as was origin of mainland USA (60.3% vs other countries/unknown 39.7%; p=0.018). No sociodemographic differences were seen for receipt of treatment, intervention or systemic therapy, for patients with early stage disease. Patients with late stage disease who had a higher level of education were more likely to receive intervention (73.0% vs no education/unknown 27.0%; p = 0.049). Receipt versus lack of systemic therapy was associated with employment status (unemployed/unknown 40.3% vs 17.5%; retired 40.3% vs 65.0%, employed 19.4% vs 17.5%; p=0.002). Median survival was not impacted by any examined sociodemographic factors.
Conclusion: Despite clear evidence of disparities in the diagnosis and care of patients with HCC in the literature, our data show that an urban academic safety net hospital is able to mitigate the impact of social determinants of health for these patients. Urban safety-net hospitals with a focus on vulnerable patient populations are able to provide outcomes on par with those seen on the national level and should serve as a care system model to address disparities in HCC care.

Introduction:
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Recently, immune checkpoint inhibitor (ICI) regimens have shown superiority to sorafenib in the first line. However, evidence of superiority of one over the other remains scarce.

Methods:
Patients with advanced HCC who received either Atezolizumab/Bevacizumab (AB) combination or Nivolumab between 2016 and 2022 were identified in our Liver Cancer Database. We performed a retrospective review of data with the aim of observing response to AB combination compared to Nivolumab alone.

Results:
A total of 96 patients received AB combination (n=61) or Nivolumab (n=35). Median age at diagnosis was 66.5 years (IQR 62-73), and 81% were white males. 76 patients classified as Child Pugh A (81%) followed by Child Pugh B (n=14, 15%). The average MELD-NA score (2016) was 9 (IQR 7-13). 63 patients had cirrhosis due to HCV (n=46, 63%), followed by EtOH (n=22, 23%). 70 patients received prior liver-directed and/or systemic therapy and 26 patients were treatment naïve. 39 had macrovascular invasion (41%) and mean pre-treatment AFP was 116 ng/mL (IQR 14-2343).

Median follow up was 19 months (IQR 22-26) and response was determined using the modified response evaluation criteria in solid tumors (mRECIST). Confirmed objective response (complete or partial) was seen in 29% (n=27) with a disease control rate of 41% (n=40).
Of the 27 patients who showed confirmed objective response, 19 received AB combination and 8 received Nivolumab. Seven out of nine patients with complete response received AB combination. Logistic regression model did not show any significant difference in response to Nivolumab vs AB combination (OR=2.8, 95% CI: 0.61-13.11, p=0.183).

Two of the complete responders with AB therapy underwent surgery after receiving immunotherapy, and histopathology from one reported no viable tumor (Figure 1).

Univariate analysis (Table 1) demonstrated an association between pre-treatment AFP >400 ng/mL and objective response (OR=4.5, 95% CI: 1.7-11.9, p=0.0015), while prior liver directed radiotherapy (OR=0.14, 95% CI: 0.01-1.1, p=0.033) or systemic chemotherapy (OR=0.25, 95% CI: 0.08-0.81, p=0.017) were associated with poor response. On multivariate analysis only AFP> 400 ng/mL remained significantly associated with response (OR=3.7, 95% CI: 1.3-10.5, p=0.014). Median overall survival at one and three years in responders was 86% and 43%, and in non-responders was 45% and 29% respectively.

Conclusion:
In our institutional experience, neither of the two treatment regimens showed statistically significant response superiority, while treatment naivety and pre-treatment AFP >400 ng/mL were associated with better objective response. Further studies aimed at identifying factors and ICI associated with better outcomes may improve survival and patient selection for these therapies.