Diffuse-Type Histology Is Prognostic for All Siewert Types of Gastroesophageal Adenocarcinoma.

PURPOSE: The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. MATERIALS AND METHODS: We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. RESULTS: Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. CONCLUSIONS: Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies.

Combined Regional Approach of Talimogene laherparepvec and Radiotherapy in the Treatment of Advanced Melanoma.

Talimogene laherparepvec (TVEC) is a genetically modified oncolytic herpes simplex virus (HSV-1) that is used for the intralesional treatment of advanced or metastatic melanoma. Given that TVEC produces the granulocyte-macrophage colony-stimulating factor (GM-CSF), recent reports have suggested that radiation treatment (RT) given in conjunction with TVEC may provide synergistic immune activation at the site, and possibly systemically. However, studies on combining RT with TVEC remain limited. We conducted a retrospective review of melanoma patients from a single cancer center who received TVEC and RT in the same region of the body and compared them to patients who received TVEC with RT at another site (other than the site of TVEC injection). Between January 2015 and September 2022, we identified twenty patients who were treated with TVEC and RT; fourteen patients received TVEC and RT in the same region, and six had treatments in separate regions. Regions were determined at the time of analysis and were based on anatomic sites (such as arm, leg, torso, etc.). Kaplan-Meier analysis of progression-free survival (PFS), analyses of time to distant metastasis (DM), overall survival (OS), and locoregional control (LRC), and the corresponding log-rank test were performed. With a median follow-up of 10.5 months [mos] (range 1.0-58.7 mos), we found an improvement in PFS with TVEC and RT in the same region compared to different regions, which were 6.4 mos (95% CI, 2.4-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively; p = 0.005. There was also a significant improvement in DM when TVEC and RT were used in the same region compared to different regions: 13.8 mos (95% CI, 4.6-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively (p = 0.001). However, we found no difference in overall survival (OS) between patients who had TVEC and RT in the same region (19.0 mos, 95% confidence interval [CI], 4.1-not reached [NR] mos) and those who received treatments in different regions (18.5 mos, 95% CI, 1.0-NR mos); p = 0.366. There was no statistically significant improvement in locoregional control (LRC) in patients who had TVEC and RT in the same region was 26.0 mos (95% CI, 6.4-26.0 mos) compared to patients who received TVEC and RT in different regions (4.4 mos) (95% CI, 0.7-NR mos) (p = 0.115). No grade 3 or higher toxicities were documented in either group. Overall, there were improvements in PFS and DM when TVEC and RT were delivered to the same region of the body compared to when they were used in different regions. However, we did not find a significant difference in locoregional recurrence or OS. Future studies are needed to assess the sequence and timing of combining RT and TVEC to potentially enhance the immune response both locally and distantly.

Conversion to open surgery in obese patients undergoing minimally invasive distal pancreatectomy: results from a multicenter analysis.

BACKGROUND: Although minimally invasive distal pancreatectomy (MIDP) is considered a standard approach it still presents a non-negligible rate of conversion to open that is mainly related to some difficulty factors, as obesity. The aim of this study is to analyze the preoperative factors associated with conversion in obese patients with MIDP. METHODS: In this multicenter study, all obese patients who underwent MIDP at 18 international expert centers were included. The preoperative factors associated with conversion to open surgery were analyzed. RESULTS: Out of 436 patients, 91 (20.9%) underwent conversion to open, presenting higher blood loss, longer operative time and similar rate of major complications. Twenty (22%) patients received emergent conversion. At univariate analysis, the type of approach, radiological invasion of adjacent organs, preoperative enlarged lymphnodes and ASA ≥ III were significantly associated with conversion to open. At multivariate analysis, robotic approach showed a significantly lower conversion rate (14.6 % vs 27.3%, OR = 2.380, p = 0.001). ASA ≥ III (OR = 2.391, p = 0.002) and preoperative enlarged lymphnodes (OR = 3.836, p = 0.003) were also independently associated with conversion. CONCLUSION: Conversion rate is significantly lower in patients undergoing robotic approach. Radiological enlarged lymphnodes and ASA ≥ III are also associated with conversion to open. Conversion is associated with poorer perioperative outcomes, especially in case of intraoperative hemorrhage.

Outpatient and Ambulatory Extended Recovery Robotic Hepatectomy: Multinational Study of 307 Cases.

BACKGROUND: For open minor hepatectomy, morbidity and recovery are dominated by the incision. The robotic approach may transform this "incision dominant procedure" into a safe outpatient procedure. STUDY DESIGN: We audited outpatient (less than 2 midnights) robotic hepatectomy at 6 hepatobiliary centers in 2 nations to test the hypothesis that the robotic approach can be a safe and effective short-stay procedure. Establishing early recovery after surgery programs were active at all sites, and home digital monitoring was available at 1 of the institutions. RESULTS: A total of 307 outpatient (26 same-day and 281 next-day discharge) robotic hepatectomies were identified (2013 to 2023). Most were minor hepatectomies (194 single segments, 90 bi-segmentectomies, 14 three segments, and 8 four segments). Thirty-nine (13%) were for benign histology, whereas 268 were for cancer (33 hepatocellular carcinoma, 27 biliary, and 208 metastatic disease). Patient characteristics were a median age of 60 years (18 to 93 years), 55% male, and a median BMI of 26 kg/m 2 (14 to 63 kg/m 2 ). Thirty (10%) patients had cirrhosis. One hundred eighty-seven (61%) had previous abdominal operation. Median operative time was 163 minutes (30 to 433 minutes), with a median blood loss of 50 mL (10 to 900 mL). There were no deaths and 6 complications (2%): 2 wound infections, 1 failure to thrive, and 3 perihepatic abscesses. Readmission was required in 5 (1.6%) patients. Of the 268 malignancy cases, 25 (9%) were R1 resections. Of the 128 with superior segment resections (segments 7, 8, 4A, 2, and 1), there were 12 positive margins (9%) and 2 readmissions for abscess. CONCLUSIONS: Outpatient robotic hepatectomy in well-selected cases is safe (0 mortality, 2% complication, and 1.6% readmission), including resection in the superior or posterior portions of the liver that is challenging with nonarticulating laparoscopic instruments.

Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database.

BACKGROUND: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated 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, we selected patients from 2004 to 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 (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching. RESULTS: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004). CONCLUSION: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.

Recurrence patterns after complex multimodality therapy and hepatic arterial infusion for colorectal liver metastases: A reflection of biology and technique.

BACKGROUND AND METHODS: We characterized colorectal liver metastasis recurrence and survival patterns after surgical resection and intraoperative ablation ± hepatic arterial infusion pump (HAIP) placement. We estimated patterns of recurrence and survival in patients undergoing contemporary multimodal treatments. Between 2017 and 2021, patient, tumor characteristics, and recurrence data were collected. Primary outcomes included recurrence patterns and survival data based on operative intervention. RESULTS: There were 184 patients who underwent hepatectomy and intraoperative ablation. Sixty patients (32.6%) underwent HAIP placement. A total of 513 metastases were ablated, median total of 2 ablations per patient. Median time to recurrence was 31 [22-40] months. Recurrence patterns included tumor at ablative margin on first scheduled postoperative imaging (8, 4.3%), local tumor recurrence at ablative site (69, 37.5%), and non-ablated liver tumor recurrence (38, 20.6%). In patients who underwent HAIP placement, the rate of liver recurrence was reduced (45% vs 70.9%, p = 0.0001). Median overall survival was 64 [41-58] months and prolonged survival was associated with HAIP treatment (85 [66-109] vs 60 [51-70] months. CONCLUSIONS AND DISCUSSION: Hepatic recurrence is common and combination of intraoperative ablation and HAIP treatments were associated with prolonged survival. These data may reflect patient selection however, future work will clarify preoperative tumor and patient characteristics that may better predict recurrence expectations.

Existing and emerging biomarkers in hepatocellular carcinoma: relevance in staging, determination of minimal residual disease, and monitoring treatment response: a narrative review.

Background and Objective: With the development of novel active systemic therapies, the landscape of hepatocellular carcinoma (HCC) management is rapidly changing. However, HCC lacks sensitive and specific biomarkers to predict prognosis, monitor for minimal residual disease after locoregional therapy, and predict treatment response. In this review, we aim to summarize the best supporting evidence for refining existing, and development of novel biomarkers for staging, prognosis, determination of minimal residual disease and monitoring treatment response in HCC, focusing on those with evidence in clinical trials. Methods: PubMed and Embase databases were searched using the keywords; hepatocellular carcinoma, biomarker, minimal residual disease, surveillance, prognosis, staging, alpha-fetoprotein (AFP), liquid biopsy, treatment response, adjuvant, immunotherapy. Relevant clinical studies were included. Key Content and Findings: AFP remains the major workhorse as the most widely used biomarker in HCC, however, its lack of wide applicability due to the high proportion of patients with HCC who are AFP negative, limits its value throughout all stages of HCC management. Significant work has been done to combine AFP with other clinical and serologic factors to increase its accuracy and utility as a biomarkers. However, it is likely that other more novel biomarkers such as those obtained through liquid biopsy will provide the prognostic power necessary for applications such as detecting recurrence and predicting treatment response. Liquid biopsy provides not only a wealth of potential biomarkers including circulating tumor cells and cell-free RNA/DNA, but also the ability to examine the mutational characteristics of the tumor with next generation sequencing. While early evidence supports the potential impact of many new biomarkers, validation in large clinical trials is lacking. Conclusions: This review highlights the paucity of sensitive and specific, widely applicable biomarkers, throughout all phases of management of HCC and summarizes evidence on biomarkers currently in use, as well as those in development and validation. Inclusion of biomarker analysis through clinical trials in HCC is critical to development of optimal therapeutic regimens, and improve patient outcomes.

METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation.

BACKGROUND: While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N6-methyladenosine (m6A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis. METHODS: Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling. RESULTS: METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s). CONCLUSIONS: Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency.

Pilot study of a telehealth intervention for personalized self-management for eating symptoms after gastroesophageal cancer surgery.

BACKGROUND AND OBJECTIVES: Following gastric and esophageal cancer surgery, patients often experience significant, prolonged eating-related symptoms. One promising approach to help patients improve their eating-related quality of life (QOL) is through self-management coaching to aid in diet modification. We performed a randomized pilot study of a nutritionist-led telehealth intervention for the self-management of eating after gastroesophageal cancer surgery. METHODS: Patients who were within 30 days of resuming oral intake after undergoing surgery for gastric and/or esophageal cancer were consented and then randomized to the intervention or usual care. The intervention was performed by a nutritionist trained in self-management coaching and delivered in four telehealth sessions over 4 months. The following outcomes were measured at baseline and at 6 months after baseline: QOL (EORTC QLQC30), weight, body mass index, and sarcopenia. RESULTS: Fifty-three patients were enrolled. 22/27 usual care and 21/26 intervention patients completed the study for a retention rate of 81%. Differences between the intervention and control groups were not statistically significant, but the intervention group had indications of greater improvements in overall QOL as measured by EORTC QLQC30 Summary Score (8.7 vs. 2.3, p = 0.17) as well as greater improvements in 4/5 functional domains (p > 0.3). The intervention group also had slightly more weight gain (6 kg vs. 3 kg, p = 0.3) and less sarcopenia (3/16 vs. 9/18, p = 0.07). CONCLUSIONS: This pilot study demonstrated the feasibility and acceptability of a telehealth intervention for self-management of eating symptoms after gastroesophageal cancer surgery. There were trends toward improved overall QOL in the intervention group. A larger study is needed to validate the results.

Robotic versus laparoscopic distal pancreatectomy for pancreatic adenocarcinoma in obese patients.

BACKGROUND: Robotic distal pancreatectomy (RDP) is associated with a lower conversion rate and less blood loss than laparoscopic distal pancreatectomy (LDP). LDP has similar oncological outcomes as open surgery in PDAC. The aim of this study was to compare perioperative and oncological outcomes in obese patients with RDP versus LDP for PDAC. MATERIALS AND METHODS: Retrospectively, all obese patients who underwent RDP or LDP for PDAC between 2012 and 2022 at 12 international expert centres were included. RESULTS: out of 372, 81 patients were included. All baseline features were comparable between the two groups. RDP was associated with decreased blood loss (495mlLDP vs. 188mlRDP; p = 0.003), lower conversion rate (13.5%RDP vs. 36.4%LDP; p = 0.019) and lower rate of Clavien-Dindo ≥3 complications (13.5%RDP vs. 36.4%LDP; p = 0.019). Overall and disease-free survival were comparable. CONCLUSIONS: In obese patients with left-sided PDAC, the robotic approach was associated with improved intraoperative outcomes and fewer severe complications.

Safe implementation of a minimally invasive hepatopancreatobiliary program, a narrative review and institutional experience.

Laparoscopic and robotic-assisted approaches to hepatopancreatobiliary (HPB) operations have expanded worldwide. As surgeons and medical centers contemplate initiating and expanding minimally invasive surgical (MIS) programs for complex HPB surgical operations, there are many factors to consider. This review highlights the key components of developing an MIS HPB program and shares our recent institutional experience with the adoption and expansion of an MIS approach to pancreaticoduodenectomy.

Robotic versus laparoscopic distal pancreatectomy in obese patients.

BACKGROUND: Although robotic distal pancreatectomy (RDP) has a lower conversion rate to open surgery and causes less blood loss than laparoscopic distal pancreatectomy (LDP), clear evidence on the impact of the surgical approach on morbidity is lacking. Prior studies have shown a higher rate of complications among obese patients undergoing pancreatectomy. The primary aim of this study is to compare short-term outcomes of RDP vs. LDP in patients with a BMI ≥ 30. METHODS: In this multicenter study, all obese patients who underwent RDP or LDP for any indication between 2012 and 2022 at 18 international expert centers were included. The baseline characteristics underwent inverse probability treatment weighting to minimize allocation bias. RESULTS: Of 446 patients, 219 (50.2%) patients underwent RDP. The median age was 60 years, the median BMI was 33 (31-36), and the preoperative diagnosis was ductal adenocarcinoma in 21% of cases. The conversion rate was 19.9%, the overall complication rate was 57.8%, and the 90-day mortality rate was 0.7% (3 patients). RDP was associated with a lower complication rate (OR 0.68, 95% CI 0.52-0.89; p = 0.005), less blood loss (150 vs. 200 ml; p < 0.001), fewer blood transfusion requirements (OR 0.28, 95% CI 0.15-0.50; p < 0.001) and a lower Comprehensive Complications Index (8.7 vs. 8.9, p < 0.001) than LPD. RPD had a lower conversion rate (OR 0.27, 95% CI 0.19-0.39; p < 0.001) and achieved better spleen preservation rate (OR 1.96, 95% CI 1.13-3.39; p = 0.016) than LPD. CONCLUSIONS: In obese patients, RDP is associated with a lower conversion rate, fewer complications and better short-term outcomes than LPD.

Different Methods of Minimally Invasive Esophagojejunostomy After Total Gastrectomy for Gastric Cancer: Outcomes from Two Experienced Centers.

BACKGROUND: Esophagojejunostomy after minimally invasive total gastrectomy (MITG) for gastric cancer (GC) is technically challenging. Failure of the esophagojejunal anastomosis can lead to significant morbidity, leading to short- and long-term quality of life (QoL) impairment or mortality. The optimal reconstruction method following MITG remains controversial. We evaluated outcomes of minimally invasive esophagojejunostomy after laparoscopic or robotic total gastrectomies. METHODS: We retrospectively reviewed MITG patients between 2015 and 2020 at two high-volume centers in China and the United States. Eligible patients were divided into groups by different reconstruction methods. We compared clinicopathologic characteristics, postoperative outcomes, including complication rates, overall survival rate (OS), disease-free survival rate (DFS), and patient-reported QoL. RESULTS: GC patients (n = 105) were divided into intracorporeal esophagojejunostomy (IEJ, n = 60) and extracorporeal esophagojejunostomy (EEJ, n = 45) groups. EEJ had higher incidence of wound infection (8.3% vs 13.3%, P = 0.044) and pneumonia (21.7% vs 40.0%, P = 0.042) than IEJ. The linear stapler (LS) group was inferior to the circular stapler (CS) group in reflux [50.0 (11.1-77.8) vs 44.4 (0.0-66.7), P = 0.041] and diarrhea [33.3 (0.0-66.7) vs 0.0 (0.0-66.7), P = 0.045] while LS was better than CS for dysphagia [22.2 (0.0-33.3) vs 11.1 (0.0-33.3), P = 0.049] and eating restrictions [33.3 (16.7-58.3) vs 41.7 (16.7-66.7), P = 0.029] at 1 year. OS and DFS did not differ significantly between LS and CS. CONCLUSIONS: IEJ anastomosis generated better results than EEJ. LS was associated with a better patient eating experience, but more diarrhea and reflux compared with CS. Clinical and patient-reported outcomes show the superiority of IEJ with the LS reconstruction method in MITG for GC.

Surgical Management of Retroperitoneal Sarcoma.

Surgery is the cornerstone of treatment for retroperitoneal sarcoma (RPS). Surgery should be performed by a surgical oncologist with sub-specialization in this disease and in the context of a multidisciplinary team of sarcoma specialists. For primary RPS, the goal of surgery is to achieve the complete en bloc resection of the tumor along with involved organs and structures to maximize the clearance of the disease. The extent of resection also needs to consider the risk of complications. Unfortunately, the overarching challenge in primary RPS treatment is that even with optimal surgery, tumor recurrence occurs frequently. The pattern of recurrence after surgery (e.g., local versus distant) is strongly associated with the specific histologic type of RPS. Radiation and systemic therapy may improve outcomes in RPS and there is emerging data studying the benefit of non-surgical treatments in primary disease. Topics in need of further investigation include criteria for unresectability and management of locally recurrent disease. Moving forward, global collaboration among RPS specialists will be key for continuing to advance our understanding of this disease and find more effective treatments.

P38 kinase in gastrointestinal cancers.

Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the advances in primary and adjuvant therapies, patients still develop distant metastases and require novel therapies. Mitogen­activated protein kinase (MAPK) cascades are crucial signaling pathways that regulate many cellular processes, including proliferation, differentiation, apoptosis, stress responses and cancer development. p38 Mitogen Activated Protein Kinases (p38 MAPKs) includes four isoforms: p38α (MAPK14), p38ß (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). p38 MAPK was first identified as a stress response protein kinase that phosphorylates different transcriptional factors. Dysregulation of p38 pathways, in particular p38γ, are associated with cancer development, metastasis, autophagy and tumor microenvironment. In this article, we provide an overview of p38 and p38γ with respect to gastrointestinal cancers. Furthermore, targeting p38γ is also discussed as a potential therapy for gastrointestinal cancers.