Developing sarcopenia during neoadjuvant therapy is associated with worse survival in esophageal adenocarcinoma patients.

BACKGROUND: Sarcopenia in cancer patients has been associated with mixed postoperative outcomes. The aim of this study was to evaluate whether the development of sarcopenia during the neoadjuvant period is predictive of postoperative mortality in esophageal adenocarcinoma patients. METHODS: We queried a prospective database to retrieve the sarcopenic status of patients with esophageal adenocarcinoma who underwent cross-sectional imaging of the third lumbar vertebra at diagnosis and within 2 months of undergoing an esophagogastrectomy between 2014 and 2022. RESULTS: Of the 71 patients included in the study, 36 (50.7%) presented with sarcopenia at diagnosis. Of the 35 non-sarcopenic patients, 14 (40%) developed sarcopenia during the neo-adjuvant period. Patients who were not sarcopenic at diagnosis but developed sarcopenia preoperatively had significantly worse overall survival than patients sarcopenic at diagnosis and not sarcopenic preoperatively and patients experiencing no change in sarcopenic status (median 18 vs 47 vs 31 months; P = .02). Diagnostic and preoperative sarcopenic status alone were not significantly associated with overall survival (P = .48 and P = .56, respectively). Although 37 (52.1%) patients died, the cause of death was often not cancer-related (54.1%) and included acute respiratory failure, pneumonia, and cardiac arrest. No significant survival difference was observed when stratified by >10% weight loss (P = .9) or large loss in body mass index (P = .8). CONCLUSION: Developing sarcopenia during the neo-adjuvant period may be associated with worse overall survival in patients requiring esophagogastrectomy.

Laparoscopic microwave ablation versus percutaneous microwave ablation of hepatic malignancies: Efficacy and recurrence-free survival outcomes in patients.

BACKGROUND: Hepatic thermal ablation has been found to be effective and equivalent to resection in certain liver histologies. Of the 16,000 annual liver ablations performed in the United States, only 13% (2,080 ablations) are performed laparoscopically. The laparoscopic technique remains underused even with the benefits of improved staging and better access to tumors. The purpose of this study is to compare laparoscopic microwave ablation versus percutaneous microwave ablation in terms of efficacy and recurrence-free survival outcomes in patients with hepatic malignancies. METHODS: A comparative analysis was performed on 275 patients (289 ablation procedures) who underwent laparoscopic microwave ablation or percutaneous microwave ablation between February 2011 and May 2021. Ablation success was confirmed postprocedure and recurrence was monitored at follow-up via contrast-enhanced computed tomography/magnetic resonance imaging and/or computed tomography/positron emission tomography. RESULTS: The groups were similar for sex, age, body mass index, location of tumor, size of tumor, and number of tumors. Ablation success was 100% in both groups. Local recurrence was significant (5%: laparoscopic microwave ablation vs 22%: percutaneous microwave ablation, P = .002) and same-lobe recurrence (21%: laparoscopic microwave ablation vs 24%: percutaneous microwave ablation) was lower in the laparoscopic microwave ablation group. Median recurrence-free survival was 15.8 months for the laparoscopic microwave ablation group and 5.6 months for the percutaneous microwave ablation group (P = .0002). Overall, 90-day complications were lower in the laparoscopic microwave ablation group (11%) compared with the percutaneous microwave ablation group (21%) (P = .11). CONCLUSION: Laparoscopic surgical ablation is a critical surgical skill that must be taught in fellowship. Laparoscopic microwave ablation leads to better tumor specific outcomes and oncologic outcomes demonstrating clinical efficacy in the treatment of hepatic malignancies compared with percutaneous microwave ablation.

Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a poor prognosis. PDAC has poor response to immunotherapy because of its unique tumour microenvironment (TME). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the TME to improve immunogenicity. Methods: In vitro human PDAC cell lines MiaPaca2 and S2-013 were treated with 5µ m 3-Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 µ m 5-Azacytidine (5-AZA, a DNMT1 inhibitor). In vivo orthotopic murine tumour models using both murine PAN02 cells and KPC cells inoculated in immunocompetent C56/BL7 mice were treated with anti-PD-L1 combined with DZNep and 5-AZA. Short hairpin knockdown (KD) of EZH2 and DNMT1 in PAN02 cells for the orthotopic murine tumour model was established to validate the drug treatment (DZNep and 5-AZA). qRT-PCR and microarray assays were performed for the evaluation of Th1-attracting chemokines and cancer-associated antigen induction. Results: Drug treatments induced significant upregulation of gene expressions of Th1-attracting chemokines, CXCL9 and CXCL10, and the cancer-testis antigens, NY-ESO-1, LAGE and SSX-4 (P < 0.05). In orthotopic tumour models, inoculation of PAN02 cells or KPC cells demonstrated significant tumour regression with corresponding increased apoptosis and infiltration of cytotoxic T lymphocytes in the combination treatment group. In the orthotopic Pan02-KD model, the anti-PD-L1 treatment also caused significant tumour regression. Conclusion: We demonstrate that immunotherapy for PDAC can be potentiated with epigenetic therapy by increasing cancer-associated antigen expression and increased T-cell trafficking across the immunosuppressive tumour microenvironment via upregulation of the repressed chemokines and increased apoptosis with subsequent tumour regression.

Enhanced recovery after surgery is safe for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is an effective, aggressive approach to treating intraperitoneal carcinomatosis. This study aimed to test the efficacy/safety of an enhanced recovery (ERAS) program after CRS-HIPEC surgery. METHODS: Review of an IRB-approved prospectively maintained HIPEC database from 2003 to 2019. Adverse events and outcomes related to the primary operation were noted. RESULTS: 125 HIPEC procedures performed met inclusion criteria, with 20 treated through ERAS. There was an improvement in LOS (ERAS: 9, 6.0-28.0; non-ERAS: 11.0, 6.0-45.1, P = 0.5), a significant reduction in opioid use during hospitalization (ERAS Total Morphine Equivalents 156 vs Non-ERAS of 856, p < 0.001), and a significant reduction in discharge opioid requirements (ERAS 55% of patients, non-ERAS 97%, p < 0.02). CONCLUSION: ERAS for CRS-HIPEC is safe, while maintaining quality outcomes, and leads to significant reductions in hospital opioid use and discharge narcotic usage. Our experience supports the full implementation of an ERAS protocol for HIPEC.

Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis.

BACKGROUND: Liver-directed hepatic arterial therapies are associated with improved survival and effective symptom control for patients with unresectable neuroendocrine liver metastases (NELM). Whether transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) with yttrium-90 (y-90) are associated with improved short- or long-term outcomes is unknown. STUDY DESIGN: A retrospective review was performed of all patients with NELM undergoing transarterial therapies, from 2000 to 2018, at 2 academic medical centers. Postoperative morbidity, radiographic response according to response evaluation criteria in solid tumors (RECIST) criteria, and long-term outcomes were compared between patients who underwent TACE vs TARE. RESULTS: Among 248 patients with NELM, 197 (79%) received TACE and 51 (21%) received TARE. While patients who underwent TACE were more likely to have carcinoid syndrome, larger tumors, and higher chromogranin A levels, there was no difference in tumor differentiation, primary site, bilobar disease, or synchronous presentation. Nearly all TARE treatments (92%) were performed as outpatient procedures, while 99% of TACE patients spent at least 1 night in the hospital. There were no differences in overall morbidity (TARE 13.7% vs TACE 22.6%, p = 0.17), grade III/IV complication (5.9% vs 9.2%, p = 0.58), or 90-day mortality. The disease control rate (DCR) on first post-treatment imaging (RECIST partial/complete response or stable disease) was greater for TACE compared with TARE (96% vs 83%, p < 0.01). However, there was no difference in median overall survival (OS, 35.9 months vs 50.1 months, p = 0.3) or progression-free survival (PFS, 15.9 months vs 19.9 months, p = 0.37). CONCLUSIONS: In this retrospective multi-institutional analysis, both TACE and TARE with Y-90 were safe and effective liver-directed therapies for unresectable NELM. Although TARE was associated with a shorter length of hospital stay, TACE demonstrated improved short-term DCR, and both resulted in comparable long term outcomes.

Should Sentinel Lymph Node Biopsy Be Performed for All T1b Melanomas in the New 8th Edition American Joint Committee on Cancer Staging System?

BACKGROUND: In the 8th edition of the American Joint Committee on Cancer melanoma staging system, the T1b category has been redefined based solely on thickness and ulceration. National Comprehensive Cancer Network guidelines recommend consideration of sentinel lymph node biopsy (SLNB) for all patients with T1b melanomas (0.8 to 1.0 mm thick). We hypothesized that the new staging system would lead to excessive use of SLNB in patients with non-ulcerated T1b melanomas with a low risk of positive sentinel lymph nodes. STUDY DESIGN: The National Cancer Database 2015 Melanoma Public Use File was used to select patients undergoing SLNB for thin T1 cutaneous melanoma from 2010 to 2015. Clinicopathologic risk factors for having a positive SLNB were evaluated. Univariable and multivariable logistic regression models and classification and regression tree analysis were performed to identify groups with high and low risk of positive SLNB. RESULTS: We selected patients undergoing SLNB without ulceration with thickness 0.75 to 1.04 mm, staged T1b in the new 8th edition American Joint Committee on Cancer by thickness criteria alone (6,894 patients). Independent risk factors for a positive sentinel lymph node were age 56 years or younger (odds ratio [OR] 1.74; 95% CI 1.38 to 2.17), thickness 1.0 vs 0.8 to 0.9 mm (OR 1.36; 95% CI 1.09 to 1.70), female sex (OR 1.36; 95% CI 1.09 to 1.69), and mitotic rate ≥1/mm2 (OR 2.01; 95% CI 1.54 to 2.64). Classification and regression tree analysis identified 2 groups based on age, mitotic rate, and thickness with a risk of positive SLNB <5%. These 2 groups made up 55% of T1b, nonulcerated melanoma patients who underwent SLNB. CONCLUSIONS: The new 8th edition American Joint Committee on Cancer melanoma staging system T1b category should not be used to determine use of SLNB in thin melanoma, as more than one half of T1b lesions without ulceration have a low risk of positive sentinel lymph nodes.

Multigene Signature Panels and Breast Cancer Therapy: Patterns of Use and Impact on Clinical Decision Making.

BACKGROUND: A growing body of evidence supports the use of multigene signature panels (MSPs) in predicting recurrence risk in patients with invasive breast cancer. This study aimed to evaluate trends in MSP use over time and the effect of MSPs on administration of postoperative chemotherapy. STUDY DESIGN: The National Cancer Database was queried for all women with invasive breast cancer who underwent resection between 2011 and 2014 and had information about performance of an MSP, hormone receptor status, and receipt of chemotherapy. Multigene signature panel use over time was evaluated, and patterns of use of Oncotype DX (ODX) and MammaPrint (MP) were compared. RESULTS: In a total of 476,128 patients, an MSP was obtained in 153,782 (30.2%). Multigene signature panel use increased over time and was associated with a decreased rate of chemotherapy administration (24.6% MSP vs 37.2% no MSP; p < 0.001). Oncotype DX remained the most common MSP used throughout the study period. Oncotype DX was used more commonly in stage I disease than MP, and MP was used more commonly in stage II and III disease. MammaPrint was more commonly used in hormone receptor-negative patients, human epidermal growth factor receptor 2-positive patients, and patients with positive lymph nodes. Postoperative chemotherapy was administered to a higher proportion of patients assessed with MP than with ODX (41.3% vs 23.4%, respectively; p < 0.001). CONCLUSIONS: Use of MSPs among patients with breast cancer has increased over time and is associated with a decreased use of adjuvant chemotherapy. Oncotype DX continues to be the most widely used MSP, although MP use has increased over time. Future studies are warranted to determine the optimal use of these MSPs in risk assessment and postoperative decision making.

Intra - operative Anesthesia Management in Patients Undergoing Surgical Irreversible Electroporation of the Pancreas, Liver, Kidney, and Retroperitoneal Tumors.

BACKGROUND: Irreversible electroporation (IRE) is a relatively new approach to the management of multiple types of locally advanced soft tissue tumors. Unique peri-procedural anesthetic management is needed in the safe and effective delivery of this therapy. OBJECTIVES: This study analyzed IRE therapy in relation to anesthetic management for our initial cohort and then established and validated a set of best practical guidelines for general anesthesia in patients undergoing IRE for abdominal tumors. PATIENTS AND METHODS: An IRB-approved prospective data collection outcome protocol was utilized. This study was broken up into two cohorts as follows: the initial 38 patients (pts) undergoing IRE in which anesthetic management was not defined or optimized and then a 40-pt validation cohort to establish the most efficacious anesthetic protocols. RESULTS: During IRE delivery, a deeper neuromuscular blockade is required to ensure that all retroperitoneal muscle excitation was minimized. In the initial 38-pt cohort, attempts to treat hypertension (median SBP 190, range 185-215 and median diastolic 98, range 91-115) were made with various types of anti-hypertensives with minimal-to-insufficient effects. The established inhalation was sevoflurane with an approximate median dose of 8.0 volume percentage. Analgesic management of continuous remifentanil was utilized with epidural management, which optimized HTN and tolerance to IRE therapy. CONCLUSIONS: Anesthetic management for IRE of soft tissue deviates from standard anesthetic medical therapy in regards to depth of neuromuscular blockade and analgesic management during IRE energy delivery. However, minor modifications in anesthesia management allow for a safe and efficient patient procedure.

Efficacy of irreversible electroporation in human pancreatic adenocarcinoma: advanced murine model.

Irreversible electroporation (IRE) is a promising cell membrane ablative modality for pancreatic cancer. There have been recent concerns regarding local recurrence and the potential use of IRE as a debulking (partial ablation) modality. We hypothesize that incomplete ablation leads to early recurrence and a more aggressive biology. We created the first ever heterotopic murine model by inoculating BALB/c nude mice in the hindlimb with a subcutaneous injection of Panc-1 cells, an immortalized human pancreatic adenocarcinoma cell line. Tumors were allowed to grow from 0.75 to 1.5 cm and then treated with the goal of complete ablation or partial ablation using standard IRE settings. Animals were recovered and survived for 2 days (n = 6), 7 (n = 6), 14 (n = 6), 21 (n = 6), 30 (n = 8), and 60 (n = 8) days. All 40 animals/tumors underwent successful IRE under general anesthesia with muscle paralysis. The mean tumor volume of the animals undergoing ablation was 1,447.6 mm(3) ± 884). Histologically, in the 14-, 21-, 30-, and 60-day survival groups the entire tumor was nonviable, with a persistent tumor nodule completely replaced fibrosis. In the group treated with partial ablation, incomplete electroporation/recurrences (N = 10 animals) were seen, of which 66% had confluent tumors and this was a significant predictor of recurrence (P < 0.001). Recurrent tumors were also significantly larger (mean 4,578 mm(3) ± SD 877 versus completed electroporated tumors 925.8 ± 277, P < 0.001). Recurrent tumors had a steeper growth curve (slope = 0.73) compared with primary tumors (0.60, P = 0.02). Recurrent tumors also had a significantly higher percentage of EpCAM expression, suggestive of stem cell activation. Tumors that recur after incomplete electroporation demonstrate a biologically aggressive tumor that could be more resistant to standard of care chemotherapy. Clinical correlation of this data is limited, but should be considered when IRE of pancreatic cancer is being considered.

Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report.

BACKGROUND: Following failure of standard systemic chemotherapy, the role of hepatic transarterial therapy for colorectal hepatic metastasis continues to evolve as the experience with this technique matures. The aim of this study to gain a better understanding of the value of drug eluting bead therapy when administered to patients with unresectable colorectal hepatic metastasis. METHODS: This was an open-label, multi-center, single arm study, of unresectable colorectal hepatic metastasis patients who had failed standard therapy from 10/2006-10/2008. Patients received repeat embolizations with Irinotecan loaded beads(max 100 mg per embolization) per treating physician's discretion. RESULTS: Fifty-five patients underwent 99 treatments using Irinotecan drug eluting beads. The median number of total treatments per patient was 2(range of 1-5). Median length of hospital stay was 23 hours(range 23 hours - 10 days). There were 30(30%) sessions associated with adverse reactions during or after the treatment. The median disease free and overall survival from the time of first treatment was 247 days and 343 days. Six patients(10%) were downstaged from their original disease status. Of these, four were treated with surgery and two with RFA.Neither number of liver lesions, size of liver lesions or extent of liver replacement(25%) were predictors of overall survival. Only the presence of extrahepatic disease(p = 0,001), extent of prior chemotherapy (failed 1st and 2nd line vs > 2 line failure)(p = 0,007) were predictors of overall survival in multivariate analysis. CONCLUSION: Chemoembolization using Irinotecan loaded beads was safe and effective in the treatment of patients as demonstrated by a minimal complication rate and acceptable tumor response.