Liver regeneration after portal and hepatic vein embolization improves overall survival compared with portal vein embolization alone: mid-term survival analysis of the multicentre DRAGON 0 cohort.

BACKGROUND: The purpose of this study was to compare 3-year overall survival after simultaneous portal (PVE) and hepatic vein (HVE) embolization versus PVE alone in patients undergoing liver resection for primary and secondary cancers of the liver. METHODS: In this multicentre retrospective study, all DRAGON 0 centres provided 3-year follow-up data for all patients who had PVE/HVE or PVE, and were included in DRAGON 0 between 2016 and 2019. Kaplan-Meier analysis was undertaken to assess 3-year overall and recurrence/progression-free survival. Factors affecting survival were evaluated using univariable and multivariable Cox regression analyses. RESULTS: In total, 199 patients were included from 7 centres, of whom 39 underwent PVE/HVE and 160 PVE alone. Groups differed in median age (P = 0.008). As reported previously, PVE/HVE resulted in a significantly higher resection rate than PVE alone (92 versus 68%; P = 0.007). Three-year overall survival was significantly higher in the PVE/HVE group (median survival not reached after 36 months versus 20 months after PVE; P = 0.004). Univariable and multivariable analyses identified PVE/HVE as an independent predictor of survival (univariable HR 0.46, 95% c.i. 0.27 to 0.76; P = 0.003). CONCLUSION: Overall survival after PVE/HVE is substantially longer than that after PVE alone in patients with primary and secondary liver tumours.

Current Status of Circulating Tumor DNA Liquid Biopsy in Pancreatic Cancer.

Pancreatic cancer is a challenging disease with a low 5-year survival rate. There are areas for improvement in the tools used for screening, diagnosis, prognosis, treatment selection, and assessing treatment response. Liquid biopsy, particularly cell free DNA liquid biopsy, has shown promise as an adjunct to our standard care for pancreatic cancer patients, but has not yet been universally adopted into regular use by clinicians. In this publication, we aim to review cfDNA liquid biopsy in pancreatic cancer with an emphasis on current techniques, clinical utility, and areas of active investigation. We feel that researchers and clinicians alike should be familiar with this exciting modality as it gains increasing importance in the care of cancer patients.

Clinical Features of Metastatic Hepatic Malignancies.

The liver is a common site for gastrointestinal tumor metastases as it is the first major organ reached by blood draining the portal venous system. With the development of more effective chemotherapeutic agents which may eradicate residual microscopic disease in the liver and help reduce known tumor burden, partial hepatectomy to remove gross metastatic disease will likely become increasingly utilized in the future. This chapter discusses the presentation and clinical factors in liver directed surgical resection.

Diagnostic laparoscopy should be performed before definitive resection for pancreatic cancer: a financial argument.

OBJECTIVES: Laparoscopy is recommended to detect radiographically occult metastases in patients with pancreatic cancer before curative resection. This study was conducted to test the hypothesis that diagnostic laparoscopy (DL) is cost-effective in patients undergoing curative resection with or without neoadjuvant therapy (NAT). METHODS: Decision tree modelling compared routine DL with exploratory laparotomy (ExLap) at the time of curative resection in resectable cancer treated with surgery first, (SF) and borderline resectable cancer treated with NAT. Costs (US$) from the payer's perspective, quality-adjusted life months (QALMs) and incremental cost-effectiveness ratios (ICERs) were calculated. Base case estimates and multi-way sensitivity analyses were performed. Willingness to pay (WtP) was US$4166/QALM (or US$50,000/quality-adjusted life year). RESULTS: Base case costs were US$34,921 for ExLap and US$33,442 for DL in SF patients, and US$39,633 for ExLap and US$39,713 for DL in NAT patients. Routine DL is the dominant (preferred) strategy in both treatment types: it allows for cost reductions of US$10,695/QALM in SF and US$4158/QALM in NAT patients. CONCLUSIONS: The present analysis supports the cost-effectiveness of routine DL before curative resection in pancreatic cancer patients treated with either SF or NAT.

Role of laparoscopy in patients with peritoneal metastases considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: We hypothesized that diagnostic laparoscopy (DL) was feasible for the evaluation of patients with peritoneal carcinomatosis (PC) undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). METHODS: A retrospective review of PC patients treated from January 2010 to April 2013 was conducted. Data on tumor characteristics, treatment details and survival outcomes were extracted and analyzed. RESULTS: Of the 101 PC patients (mean age 52.9 ± 14.1 years), 73 diagnostic laparoscopies DL (61 concurrent with CRS + HIPEC) were performed in 70 patients whereas 31 patients underwent direct exploratory laparotomy (EL). Complete laparoscopic assessment was possible in 63 cases (86.3%), resulting in 18 exclusions (27.7%) while 10 cases were converted to open due to inadequate laparoscopic visualization. Subsequently, CRS + HIPEC was performed in 85.4% (of 55 selected for HIPEC, DL) versus 74.2% (EL, P value = 0.20). Among those excluded from HIPEC at the initial operation, delayed HIPEC after conversion chemotherapy was achieved in 6 (of 11 with extensive disease, DL). The incidence of grade 3 to 5 complications was 0% DL versus 10% EL (P value = 0.2). There were no port site recurrences at mean follow up of 9.1 ± 8 months. CONCLUSIONS: Laparoscopy is a feasible technique for selecting patients with PC for CRS + HIPEC, and can help select patients for conversion chemotherapy in the setting of high peritoneal carcinomatosis index (PCI) score.

Staging chest computed tomography and positron emission tomography in patients with pancreatic adenocarcinoma: utility or futility?

OBJECTIVES: This study was conducted to determine if routine staging chest computed tomography (CT) or positron emission tomography (PET) scanning alters the clinical management of patients with newly diagnosed pancreatic adenocarcinoma. METHODS: All new pancreas cancers seen in medical oncology, radiation oncology and surgery from 1 June 2008 to 20 June 2010 were retrospectively reviewed. Patients with metastatic disease on chest CT or PET, that had been unsuspected on initial imaging, were identified. RESULTS: Pancreatic adenocarcinoma was present in 247 consecutive patients. Abdominal CT demonstrated metastases in 108 (44%) and localized disease in 139 (56%) patients. Chest CT and PET were not performed in 15 (11%) of these 139 patients. In the remaining 124 patients, CT imaging suggested resectable disease in 46, borderline resectable disease in 52 and locally advanced disease in 26 patients. Chest CT demonstrated an unsuspected lymphoma in one patient with borderline resectable disease and PET identified extrapancreatic disease in two patients with locally advanced disease. Chest CT and PET added no information in 121 (98%) of the 124 patients. CONCLUSIONS: The addition of chest CT and PET to high-quality abdominal CT is of little clinical utility; additional sites of metastasis are rarely found. As the quality of abdominal imaging declines, the yield from other imaging modalities will increase. Dedicated pancreas-specific abdominal CT remains the cornerstone of initial staging in suspected or biopsy-proven pancreatic cancer.

Borderline resectable/locally advanced pancreatic adenocarcinoma: improvements needed in population-based registries.

BACKGROUND: Management of patients with borderline resectable/locally advanced (BR/LA) pancreatic adenocarcinoma is based on knowledge of natural history and patterns of treatment failure, information of great importance to large data registries. Using the SEER database, we examined the survival for patients with BR/LA tumors and critically evaluated the utility of the data. METHODS: T3/T4 tumors from 2004 to 2007 were divided into those that involved the portal vein/superior mesenteric vein/gastroduodenal artery/hepatic artery and those that involved the superior mesenteric artery (SMA) or celiac axis. The control group (CG) included patients who were recommended surgery but did not undergo it. Multivariate disease-specific survival analyses were performed using the Cox proportional hazards model. RESULTS: Of 3,837 patients, 571 patients (15 %) were recommended surgery, and 323 (8 %) underwent surgical resection. We were unable to separate patients into BR/LA based on current NCCN guidelines. We were able to identify vascular involvement but not those who actually underwent vascular resection. Median survival of patients who underwent surgery with SMA and celiac involvement was 12 and 8 months compared with 7 and 6 months, respectively, in the CG (p = .01). Patients who underwent surgical resection with venous involvement had a longer survival than those with arterial involvement (18 vs 12 months, p = .001). CONCLUSIONS: Analysis of patients with BR/LA pancreatic adenocarcinoma who underwent pancreatic resection in the SEER database yielded limited information. New manuals must focus on obtaining information consistent with current advances in the field; our recommendations for optimizing the SEER database are included.

Recurrence after microwave ablation of liver malignancies: a single institution experience.

BACKGROUND: Microwave ablation (MWA) is increasingly used to achieve local control for liver tumours. This study sought to examine a monocentric experience with MWA, with a primary hypothesis that primary tumour histology was a significant predictor of early recurrence. METHODS: Retrospective single-institution review identified consecutive patients with liver tumours treated by MWA. Cox proportional hazards models assessed significance of prognostic variables. RESULTS: Seventy-two patients (43 female, 60%) underwent 83 MWA procedures for 157 tumours. Tumour histologies included hepatocellular cancer (10 operations), colorectal metastases (39), metastatic carcinoid (20) and other (14). The median tumour size was 2.0 cm. A concomitant liver resection was performed in 50 cases (60%). Crude peri-operative morbidity and mortality rates were 16% and 1%, respectively. The median follow-up was 16 months. Ablations were complete for 149 out of 157 tumours (95%). The median overall and recurrence-free survivals were 36 and 18 months, respectively. There was no difference in time to recurrence between the primary tumour types. In multivariable models, recurrence-free survival was independently associated with the use of neoadjuvant [hazard ratio (HR): 2.90, 95% confidence interval (CI): 1.09-7.76, P = 0.034] and adjuvant chemotherapy (HR: 0.36, 95% CI: 0.15-0.82, P = 0.016). CONCLUSIONS: MWA is a safe and feasible approach for local control of liver tumours. While chemotherapy administration was associated with time to recurrence after MWA, larger studies are needed to corroborate these findings.

Sarcoidosis of the Bile Duct.

Sarcoidosis is an inflammatory disease that affects multiple organs. The lungs are the most commonly involved organs. Although a large proportion of patients with sarcoidosis have liver involvement, bile duct involvement is rare. Here, we present a case of a 56-year-old African American patient presented with painless jaundice because of extrahepatic bile duct sarcoidosis. Our diagnostic approach using endoscopic cholangioscopy with targeted biopsies confirmed the diagnosis. Multiple bile duct stent exchanges were performed to manage the bile duct stricture in addition to medical therapy.

Effect of Operative Time on Outcomes of Minimally Invasive Versus Open Pancreatoduodenectomy.

OBJECTIVE: To evaluate how operative time interacts with outcomes among different approaches to pancreaticoduodenectomy (PD). Minimally invasive PDs (MIPD), which include laparoscopic (LPD) and robotic (RPD) approaches, are increasingly performed in the USA. MIPD are generally associated with longer operative times (OT) compared to open PD (OPD). Increased OT is associated with inferior outcomes for OPD; however, the effect of OT on MIPD is not well understood. METHODS: National Surgical Quality Improvement Program (NSQIP)-targeted pancreatectomy dataset was utilized (2014-2019). Propensity score matching, logistic regression, and mixed effect modeling were performed to determine the effect of OT on outcomes following PD. OTs were stratified by quartiles for each approach, and outcomes were subsequently compared. RESULTS: Among 23,988 PDs, 22,185 were OPD and 1803 MIPD. Increased OT was associated with greater overall morbidity in all approaches. When comparing OT quartiles, MIPD was consistently associated with improved overall morbidity compared to OPD in matched cohorts. However, for upper quartiles, prolonged OT in MIPD was associated with significantly increased reoperation rates and mortality. The effect of OT on overall morbidity and other outcomes was comparable among LPD and RPD. CONCLUSIONS: In this study, increased OT was associated with incremental increases in overall morbidity after PD, irrespective of approach. While MIPD was associated with improved overall morbidity compared to OPD when stratified by OT quartile, higher mortality rates were observed with prolonged OT only with MIPD. Those data suggest that MIPD is a safe alternative to OPD when OT is optimized. NSQIP was used to compare the effect of operative time (OT) on outcomes following pancreaticoduodenectomy (PD), stratified by approach. Increased OT was associated with inferior outcomes following open, laparoscopic, and robotic PD. Surgeons should attempt to optimize OT, regardless of the approach to PD.

Importance of histologic subtype in the staging of appendiceal tumors.

BACKGROUND: Malignant neoplasms of the appendix have different behavior based on their histologic subtypes in anecdotal series. Current staging systems do not capture the diversity of histologic subtypes in predicting outcomes. METHODS: We queried all patients with appendiceal malignancies captured in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2007. Tumors were classified as colonic type adenocarcinoma, mucinous adenocarcinoma, signet ring cell type, goblet cell carcinoid, and malignant carcinoid. We compared incidence, overall survival, and disease-specific survival for these tumors on the basis of patient, tumor, and therapy characteristics. Estimates from Cox proportional hazard modeling were used to predict hazard ratios for differing histologic subtypes with similar tumor, node, metastasis system (TNM) stages. RESULTS: Of the 5672 patients identified, we included 5655 (99%) in our analysis. The 5-year disease-specific survival rates were 93% for malignant carcinoid, 81% for goblet cell carcinoid, 55% for colonic type adenocarcinoma, 58% for mucinous adenocarcinoma, and 27% for signet ring cell type. Predicted estimates of adjusted hazard ratios revealed an 8-fold difference between histologic subtypes for similar TNM stages. CONCLUSIONS: Histologic subtype is an important predictor of disease-specific survival and overall survival in patients with appendiceal neoplasms. Addition of the histologic subtype to the TNM staging is simple and may improve prognostication.

Refining colorectal cancer classification and clinical stratification through a single-cell atlas.

BACKGROUND: Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. RESULTS: Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. CONCLUSIONS: Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.

Cost-effectiveness of prolonged thromboprophylaxis after cancer surgery.

BACKGROUND: Consensus guidelines recommend prolonged thromboprophylaxis for up to 4 weeks after major abdominopelvic cancer operations. Several factors impede widespread adoption of these guidelines. These include lack of awareness, cost, increased bleeding complications, increased incidence of heparin-induced thrombocytopenia, and poor patient compliance. METHODS: A cost-effectiveness model was constructed comparing four potential strategies to postdischarge thromboprophylaxis in surgical oncology patients: (1) low-molecular-weight heparin (LMWH) once daily; (2) low-dose unfractionated heparin (LDUH) three times daily; (3) oral aspirin once daily; or (4) no prolonged prophylaxis. Probabilities and costs were estimated on the basis of published literature and average Medicare reimbursement. The decision analysis was conducted from the perspective of the health care system, with the primary end point being cost per patient without venous thromboembolism (VTE). Sensitivity analyses tested the robustness of the results. RESULTS: LDUH was most cost-effective, saving $154 per patient without VTE compared with no prophylaxis. LMWH was not cost-effective, incurring a cost of $230 per patient without VTE compared with no prophylaxis. Aspirin was a viable alternative to LDUH, saving $123 compared with no prophylaxis. When poor compliance was considered, aspirin became the dominant strategy. Sensitivity analyses failed to show any instance where LMWH was cost-effective. In terms of population costs, widespread use of LDUH after discharge would save $30.3 million per year in the United States. CONCLUSIONS: Although all chemical prophylaxis is effective in preventing VTE in the outpatient setting after cancer surgery, either LDUH or aspirin are the most cost-effective, depending on patient compliance.

National Treatment Practice for Adrenocortical Carcinoma: Have They Changed and Have We Made Any Progress?

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials. METHODS: The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created. RESULTS: From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03). CONCLUSIONS: Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.

Evolving Clinical Utility of Liquid Biopsy in Gastrointestinal Cancers.

Room for improvement exists regarding recommendations for screening, staging, therapy selection, and frequency of surveillance of gastrointestinal cancers. Screening is costly and invasive, improved staging demands increased sensitivity and specificity to better guide therapy selection. Surveillance requires increased sensitivity for earlier detection and precise management of recurrences. Peripherally collected blood-based liquid biopsies enrich and analyze circulating tumor cells and/or somatic genomic material, including circulating tumor DNA along with various subclasses of RNA. Such assays have the potential to impact clinical practice at multiple stages of management in gastrointestinal cancers. This review summarizes current basic and clinical evidence for the utilization of liquid biopsy in cancers of the esophagus, pancreas, stomach, colon, and rectum. Technical aspects of various liquid biopsy methodologies and targets are reviewed and evidence supporting current commercially available assays is examined. Finally, current clinical applicability, potential future uses, and pitfalls of applying liquid biopsy to the screening, staging and therapeutic management of these diseases are discussed.

Primary Tumor Site Affects Survival in Patients with Gastroenteropancreatic and Neuroendocrine Liver Metastases.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are commonly present with metastatic disease, and the liver is the most frequent metastatic site. Herein, we studied whether primary tumor site affects survival in patients with GEP-NETs and liver metastases (NELM). As a secondary endpoint, we studied whether extrahepatic disease and surgical resection impact survival in this patient population. METHODS: Patients with NELM diagnosed from 2006 to 2014 were identified from the National Cancer Database. Kaplan-Meier curves and nested Cox proportional hazards were used to assess variables associated with survival. RESULTS: 2947 patients with well- or moderately differentiated GEP-NETs and NELM met the inclusion criteria for this study. Patients with small bowel NETs survived the longest of all GEP-NETs with NELM (median not reached). Rectal and gastric NETs with NELM had the shortest survival (median 31 months). Patients with extrahepatic metastases who underwent any operation survived longer than those managed nonoperatively (median survival 38.7 months vs. 18.6 months, p = 0.01). On multivariable analysis, operations on the primary tumor and distant metastatic site (HR 0.23-0.43 vs. no surgery), treatment at an academic/research hospital, Charlson comorbidity index of 0, no extrahepatic metastases, and younger age were associated with prolonged survival (p < 0.01). CONCLUSIONS: Primary tumor site affects survival in patients with GEP-NETs and NELM. Surgical resection seems beneficial for all GEP-NETs with NELM, even in the presence of extrahepatic metastases.

68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) changes management in a majority of patients with neuroendocrine tumors.

BACKGROUND: 68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) has shown superior accuracy in detecting grade 1 and 2 neuroendocrine tumors over previous imaging modalities and was recently included in National Comprehensive Cancer Network guidelines. It remains unclear which patients benefit most from this imaging modality. We therefore reviewed our initial experience with 68Gallium-DOTATATE PET CT to evaluate its usefulness in diagnosing, staging, and surveilling neuroendocrine tumors. METHODS: Records of patients who underwent 68Gallium-DOTATATE PET CT from March to December 2017 were prospectively evaluated. The primary endpoint was whether 68Gallium-DOTATATE PET CT changes treatment in patients with neuroendocrine tumors. Descriptive statistics, Fisher exact tests, and nested logistic regressions were conducted. RESULTS: A total of 50 consecutive patients were included. Of these, 41 patients (82%) had a biopsy-proven neuroendocrine tumor at the time of imaging. The remaining 9 patients (18%) had symptoms or biochemistry suggestive of a neuroendocrine tumor with negative cross-sectional imaging. 68Gallium-DOTATATE PET CT changed management in 33 patients (66%). There were 24 patients with intermodality changes in management and 9 patients with intramodality changes in management. Patients with scans performed for staging had a higher likelihood of a change in management (P = .006). CONCLUSION: Performing 68Gallium-DOTATATE PET CT should be considered for staging and surveillance of neuroendocrine tumors because it is frequently associated with changes in management.