Recurrence and tumor-related death after resection of hepatocellular carcinoma in patients with metabolic syndrome.

Background & Aims: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. Methods: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. Results: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002). Conclusions: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. Impact and implications: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

Minimally Invasive Versus Open Liver Resections for Hepatocellular Carcinoma in Patients With Metabolic Syndrome.

OBJECTIVE: To compare minimally invasive (MILR) and open liver resections (OLRs) for hepatocellular carcinoma (HCC) in patients with metabolic syndrome (MS). BACKGROUND: Liver resections for HCC on MS are associated with high perioperative morbidity and mortality. No data on the minimally invasive approach in this setting exist. MATERIAL AND METHODS: A multicenter study involving 24 institutions was conducted. Propensity scores were calculated, and inverse probability weighting was used to weight comparisons. Short-term and long-term outcomes were investigated. RESULTS: A total of 996 patients were included: 580 in OLR and 416 in MILR. After weighing, groups were well matched. Blood loss was similar between groups (OLR 275.9±3.1 vs MILR 226±4.0, P =0.146). There were no significant differences in 90-day morbidity (38.9% vs 31.9% OLRs and MILRs, P =0.08) and mortality (2.4% vs 2.2% OLRs and MILRs, P =0.84). MILRs were associated with lower rates of major complications (9.3% vs 15.3%, P =0.015), posthepatectomy liver failure (0.6% vs 4.3%, P =0.008), and bile leaks (2.2% vs 6.4%, P =0.003); ascites was significantly lower at postoperative day 1 (2.7% vs 8.1%, P =0.002) and day 3 (3.1% vs 11.4%, P <0.001); hospital stay was significantly shorter (5.8±1.9 vs 7.5±1.7, P <0.001). There was no significant difference in overall survival and disease-free survival. CONCLUSIONS: MILR for HCC on MS is associated with equivalent perioperative and oncological outcomes to OLRs. Fewer major complications, posthepatectomy liver failures, ascites, and bile leaks can be obtained, with a shorter hospital stay. The combination of lower short-term severe morbidity and equivalent oncologic outcomes favor MILR for MS when feasible.

Model to predict major complications following liver resection for HCC in patients with metabolic syndrome.

BACKGROUND: Metabolic syndrome (MS) is rapidly growing as risk factor for HCC. Liver resection for HCC in patients with MS is associated with increased postoperative risks. There are no data on factors associated with postoperative complications. AIMS: The aim was to identify risk factors and develop and validate a model for postoperative major morbidity after liver resection for HCC in patients with MS, using a large multicentric Western cohort. MATERIALS AND METHODS: The univariable logistic regression analysis was applied to select predictive factors for 90 days major morbidity. The model was built on the multivariable regression and presented as a nomogram. Performance was evaluated by internal validation through the bootstrap method. The predictive discrimination was assessed through the concordance index. RESULTS: A total of 1087 patients were gathered from 24 centers between 2001 and 2021. Four hundred and eighty-four patients (45.2%) were obese. Most liver resections were performed using an open approach (59.1%), and 743 (68.3%) underwent minor hepatectomies. Three hundred and seventy-six patients (34.6%) developed postoperative complications, with 13.8% major morbidity and 2.9% mortality rates. Seven hundred and thirteen patients had complete data and were included in the prediction model. The model identified obesity, diabetes, ischemic heart disease, portal hypertension, open approach, major hepatectomy, and changes in the nontumoral parenchyma as risk factors for major morbidity. The model demonstrated an AUC of 72.8% (95% CI: 67.2%-78.2%) ( https://childb.shinyapps.io/NomogramMajorMorbidity90days/ ). CONCLUSIONS: Patients undergoing liver resection for HCC and MS are at high risk of postoperative major complications and death. Careful patient selection, considering baseline characteristics, liver function, and type of surgery, is key to achieving optimal outcomes.

Small Bowel Evisceration Through a Perforated Stercoral Ulcer.

Stercoral ulcers are localized areas of loss of colonic mucosal integrity. They result from pressure necrosis of the colonic mucosa, secondary to chronic constipation and fecal inspissation. These ulcers are rare and, are associated with serious complications, including bleeding and perforation. We present the case of a 50-year-old woman who presented with small bowel evisceration through the anal canal secondary to extraperitoneal perforation of the rectum. The patient underwent emergent exploratory laparotomy with reduction of the bowel, followed by second look laparotomy in 24 hours. A full thickness defect in the rectum was identified and Hartmann's procedure was performed. The patient's postoperative course was uneventful. Extraperitoneal perforation and evisceration of bowel is a rare clinical entity. These cases are diagnosed early due to the obvious clinical presentation and however may be misdiagnosed as prolapse. They necessitate urgent and careful surgical planning, to ensure preservation of bowel and complete recovery.

Management of Massive Upper Gastrointestinal Hemorrhage Secondary to Gastrosplenic Fistula.

Gastrosplenic fistula (GSF) is seen secondary to the development of a fistulous track between the stomach and spleen and/or splenic vessels. It is most commonly seen in patients with diffuse B-cell lymphoma, who usually present with symptoms of abdominal pain and weight loss. GSF has also been seen in patients with gastric adenocarcinoma, Hodgkin's lymphoma, peptic ulcer disease, splenic abscesses, and post gastric sleeve resection. Less than 25% of the patients with GSF may present with upper gastrointestinal bleed (UGIB). This presentation of GSF is common with benign causes including peptic ulcer disease. UGIB secondary to GSF, while rare, requires prompt identification and intervention, to avoid catastrophic outcomes. We discuss the case of a 64-year-old female with GSF, who presented with sentinel bleed followed by hemorrhagic shock, secondary to a B-cell lymphoma, who was managed with a partial gastrectomy, splenectomy, and distal pancreatectomy, with favorable outcomes.

Impact of Neoadjuvant Therapy on Survival Following Margin-Positive Resection for Pancreatic Cancer.

INTRODUCTION: A positive microscopic margin (R1) following resection of pancreatic ductal adenocarcinoma (PDAC) can occur in up to 80% of patients and is associated with reduced survival and increased recurrence. Our aim was to characterize the impact of neoadjuvant therapy (NAT) on survival and recurrence in patients with PDAC following an R1 resection. METHODS: A retrospective analysis of patients with PDAC who underwent pancreatectomy from 2008 to 2017 was performed. Patients were staged according to the American Joint Committee on Cancer 8th edition and stratified based on resection margin (R0 vs. R1) and treatment sequence (NAT vs. surgery first [SF]). Conditional survival analysis was performed using Cox regression and inverse probability weighted estimates. RESULTS: Among 580 patients, 59% received NAT and 41% underwent SF. On final pathology, the NAT cohort had smaller tumors and less lymph node (LN) positivity (p < 0.05). NAT was not associated with an R1 resection (50%, p = 0.653). Compared with the R1 cohort, the R0 cohort had a higher median overall survival (OS; 39.6 vs. 22.8 months; hazard ratio [HR] 1.6, p < 0.001) and disease-free survival (DFS; 19 vs. 13 months; HR 1.35, p = 0.004). After risk adjustment, NAT was not associated with OS, regardless of margin status (R0, 95% confidence interval [CI] (-)7.31-27.07, p = 0.26; or R1, 95% CI (-)36.99-15.25, p = 0.42). However, NAT was associated with improved DFS in the R1 cohort (95% CI 1.79-11.91, p = 0.008) but not in the R0 cohort (95% CI (-)11.22-10.54, p = 0.95). CONCLUSION: An R0 resection remains an important determinant of overall and disease-free survival, even when NAT is administered. For patients with an R1 resection, receipt of NAT may prolong DFS.

Baseline Plasma Inflammatory Profile Is Associated With Response to Neoadjuvant Chemotherapy in Patients With Pancreatic Adenocarcinoma.

Despite its increased application in pancreatic ductal adenocarcinoma (PDAC), complete response to neoadjuvant therapy (NAT) is rare. Given the critical role of host immunity in regulating cancer, we sought to correlate baseline inflammatory profiles to significant response to NAT. PDAC patients receiving NAT were classified as responders (R) or nonresponders (NR) by carbohydrate antigen 19-9 response, pathologic tumor size, and lymph node status in the resected specimen. Baseline (treatment-naive) plasma was analyzed to determine levels of 27 inflammatory mediators. Logistic regression was used to correlate individual mediators with response. Network analysis and Pearson correlation maps were derived to determine baseline inflammatory mediator profiles. Forty patients (20R and 20NR) met study criteria. The R showed significantly higher overall survival (59.4 vs. 21.25 mo, P=0.002) and disease-free survival (50.97 vs. 10.60 mo, P=0.005), compared with NR. soluble interleukin-2 receptor alpha was a significant predictor of no response to NAT (P=0.045). Analysis of inflammatory profiles using the Pearson heat map analysis followed by network analysis depicted increased inflammatory network complexity in NR compared with R (1.69 vs. 1), signifying a more robust baseline inflammatory status of NR. A panel of inflammatory mediators identified by logistic regression and Fischer score analysis was used to create a potential decision tree to predict NAT response. We demonstrate that baseline inflammatory profiles are associated with response to NAT in PDAC, and that an upregulated inflammatory status is associated with a poor response to NAT. Further analysis into the role of inflammatory mediators as predictors of chemotherapy response is warranted.

Predictors of early recurrence following neoadjuvant chemotherapy and surgical resection for localized pancreatic adenocarcinoma.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (NAT) for pancreatic adenocarcinoma (PDAC) is increasingly being utilized. However, a significant number of patients will experience early recurrence, possibly negating the benefit of surgery. We aimed to identify factors implicated in early disease recurrence. METHODS: A retrospective review of pancreaticoduodenectomies performed between 2005 and 2017 at our institution for PDAC following NAT was performed. A 6-month cut-off was used to stratify patients into early/late recurrence groups. Multivariate analysis was performed to identify predictors of recurrence. RESULTS: Of 273 patients, 64 (23%) developed early recurrence or died within 90 days of surgery. The median time to recurrence was 4 months (95% confidence interval [CI]: 2.2-4.3) in the early group versus 16 months (95% CI: 13.7-19.9) in the late group. The former had higher baseline and post-NAT Ca19-9 levels than the latter (472 vs. 153 IU/ml, p = 0.001 and 71 vs. 39 IU/ml, p = 0.005, respectively). A higher positive lymph node ratio significantly increased the risk of early recurrence (hazard ratio [HR]: 15.9, p < 0.001) while adjuvant chemotherapy was protective (HR: 0.4, p < 0.001). CONCLUSION: Our findings acknowledge the limitations of clinically measured factors used to ascertain response to NAT and underline the need for individualized molecular markers that take into consideration the specific tumor biology.

Perioperative and oncologic outcomes of open, laparoscopic, and robotic distal pancreatectomy for pancreatic adenocarcinoma.

The utilization of minimally invasive distal pancreatectomy (MIDP) is increasing, yet debate remains regarding its oncologic safety in the setting of pancreatic adenocarcinoma (PDAC). Herein we present our institutional experience with robotic (RDP), laparoscopic (LDP), and open distal pancreatectomy (ODP) in the setting of PDAC.Retrospective review of a prospectively collected single institutional database of patients undergoing consecutive ODP, LDP, and RDP for left-sided PDAC between January 2008 and December 2019 at the University of Pittsburgh Medical Center (UPMC) was done. Perioperative and postoperative outcomes were compared using non-parametric testing and Fischer exact or chi-squared testing. Kaplan-Meier survival curves for disease-free survival and overall survival were compared by Log-Rank sum test. Backward Cox-proportional hazard regression analysis was used to determine if the operative approach was an independent predictor of recurrence and overall survival.Over 12 years, 146 consecutive distal pancreatectomies for PDAC were performed, of which 28.1% ODP, 60.3% RDP, and 11.6% LDP. There were no statistical differences in patients' baseline characteristics, including gender, comorbidities, prior abdominal surgeries, and AJCC8th stage (p > 0.05). Postoperatively, there was no difference in the frequency of major complications (p = 0.414), CR-POPF (p = 0.563), or DGE (p = 0.179). The median overall survival was 28.4 months for ODP, 34.6 months for RDP, and 32.5 months for LDP (Log Rank p = 0.914). On multivariate Cox proportional hazard analysis, the surgical approach was not associated with overall survival. This comparative analysis suggests a non-inferiority of RDP platforms, compared to LDP and classic ODP. The merits of MIS pancreatic surgery in the setting of PDAC should be evaluated in future prospective studies with care to analyze RDP outcomes separately from LDP.

Outcomes of Neoadjuvant Chemotherapy Versus Chemoradiation in Localized Pancreatic Cancer: A Case-Control Matched Analysis.

BACKGROUND: Neoadjuvant therapy is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). It is unknown whether neoadjuvant chemoradiotherapy is more effective than chemotherapy (NCRT vs. NAC). We aim to compare pathological and survival outcomes of NCRT and NAC in patients with PDAC. PATIENTS AND METHODS: Single-center analysis of PDAC patients treated with NCRT or NAC followed by resection between December 2008 and December 2018 was performed. Average treatment effect (ATE) was estimated after case-control matching using Mahalanobis distance nearest-neighbor matching. Inverse probability weighted estimates (IPWE)-based ATE was estimated for disease-free survival (DFS) and overall survival (OS). RESULTS: Among the 418 patients (mean age 66.8 years, 51% female) included in the study, 327 received NAC and 91 received NCRT. NCRT patients had higher rates of locally advanced disease, number of neoadjuvant chemotherapy cycles, more chemotherapy regimen crossover (gemcitabine and 5-FU based), and were more likely to undergo open surgical procedures and/or vascular resection (all p < 0.05). After matched analysis, NCRT was associated with a significant reduction in lymph node positive disease [ATE = (-)0.24, p = 0.007] and lymphovascular invasion [ATE = (-)0.20, p = 0.02]. While NCRT was associated with significantly improved DFS by 9.5 months (p = 0.006), it did not affect OS by IPWE-based ATE after adjusting for adjuvant therapy (ATE = 5.5 months; p = 0.32). CONCLUSION: Compared with NAC alone, NCRT is associated with improved pathologic surrogates and disease-free survival, but not overall survival in patients with PDAC.

Long-Term Surgical Complications After Pancreatoduodenectomy: Incidence, Outcomes, and Risk Factors.

BACKGROUND: Long-term complications following pancreatoduodenectomy (PD) can significantly impact quality of life and healthcare utilization. Most reports focus on short-term (within 90 days) PD outcomes; however, the incidence and risk factors for long-term complications (> 90 days) remain to be evaluated. We sought to identify the incidence, outcomes, and risk factors for long-term complications post-PD. METHODS: All PD survivors between 2010 and 2017 were identified from a single-institutional database. Long-term complications (> 90 days post-PD and not resulting from cancer recurrence), including biliary stricture, cholangitis, pancreatitis, peptic ulcer, small bowel obstruction, and incisional hernia, were identified. Logistic regression was used to identify perioperative predictors of long-term complications. RESULTS: Of 906 PDs, 628 long-term survivors met criteria for analysis (mean age of 65.3 years, 47% female). Median follow-up and overall survival were 51.1 months (95% CI 47.6, 55.7) and 68.5 months (95% CI 57.9, 81.4), respectively. A total of 198 (31.5%) experienced at least one long-term complication. Complications included incisional hernia (17.7%), biliary stricture or cholangitis (8.0%), pancreatitis (5.7%), small bowel obstruction (4.3%), and peptic ulcer (3.2%). In total, 108 (17.2%) of the complications required an intervention, nearly half of which were surgical. On multivariable analysis, several predictors of long-term complications were identified: obesity (BMI ≥ 30 kg/m2), postoperative wound infection, prolonged index length of stay, readmission (< 90 days), operative approach (open vs. robotic), and pylorus-preservation. CONCLUSION: Long-term complications occur in nearly a third of PDs and nearly one-fifth of all PDs require re-intervention. Several modifiable predictors of long-term complications were identified.

Pathology of Melanoma.

Melanoma is an aggressive malignancy arising from melanocytes in the skin and rarely in extracutaneous sites. The understanding of pathology of melanoma has evolved over the years, with the initial classifications based on the clinical and microscopic features to the current use of immunohistochemistry and genetic sequencing. The depth of invasion and lymph node metastasis are still the most important prognostic features of melanoma. Other important prognostic features include ulceration, lymphovascular invasion, mitosis, and tumor-infiltrating lymphocytes. This article reviews the pathology of melanoma and its precursor lesions, along with the recent advances in pathologic diagnosis of melanoma.