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Introduction: Prior work has established hyperthermic intraperitoneal chemotherapy (HIPEC) administration as a safe treatment option for select patients with gastric adenocarcinoma and carcinomatosis. However, identifying patients who will maximally benefit from HIPEC remains unclear. This study assessed a single-institution experience with HIPEC for metastatic gastric cancer to identify variables associated with improved survival., Methods: A database of patients treated for metastatic gastric adenocarcinoma at MD Anderson Cancer Center from 2013 to 2022 was queried for patients undergoing HIPEC as part of their treatment regimen. Patients were stratified by overall survival (OS)≥36 months or <36 months and assessed along demographic and clinicopathologic variables to identify factors associated with OS ≥ 36 months., Results: Among 104 patients, 1,2, and 3-year OS from diagnosis was 89 %,44 %, and 18 %. Patients with OS ≥ 36 months were more likely to have moderately differentiated tumors, positive cytology only (i.e. no visible carcinomatosis), and lower peritoneal cancer index (PCI) than those with OS < 36 months (p = 0.002, p = 0.01, p = 0.001,respectively). Groups did not otherwise differ with respect to demographic parameters or treatment or pathologic details. Among patients who underwent gastrectomy, those with OS < 36 months had higher pathologic T and N category (p = 0.003 and p = 0.02, respectively). Postoperative mortality was zero in both groups among patients undergoing gastrectomy., Conclusions: HIPEC may provide more durable survival benefit among patients with metastatic gastric cancer with moderately differentiated disease, low PCI, and positive cytology alone. Additionally, among patients who undergo gastrectomy, higher final pathologic T and N category are associated with worse survival. Trials are needed to compare 3-year OS rates in patients treated with HIPEC versus systemic therapy alone., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose of Review: This study aims to present the current landscape of immunotherapy in the management of small bowel neuroendocrine tumors and identify ongoing and future targets for improved response., Recent Findings: Somatostatin analogs and mTOR inhibitors remain cornerstones of non-surgical treatment, and applications of PRRT in SBNET are promising. Several efforts to replicate the success of immunotherapies in other solid tumors have been attempted in SBNET, with limited responses observed with current immune targets, such as PD-1/PD-L1 and CTLA-4. Epigenetic analyses have suggested a potential role for methylation and histone acetylation in SBNET tumorigenesis that warrant greater exploration. While the incidence of SBNET continues to increase, the number of effective therapies is few. Further elucidation of targetable components of the SBNET immune microenvironment with greater modulatory effects is necessary to improve outcomes in this growing patient population., Competing Interests: Declarations. Human and Animal Rights and Informed Consent: To the best of their knowledge, the authors confirm that the human subject studies referenced in this article were performed in accordance with the guidelines specified by the Declaration of Helsinki and the appropriate institutional review boards. Conflicts of Interest: Brittany C. Fields, Reed I. Ayabe, Y. David Seo, and Jessica E. Maxwell declare no conflicts of interest. Daniel M. Halperin has received clinical trial funding from Genentech/Roche; RayzeBio, and Thermo Fisher Scientific; grants and personal fees from AAA/Novartis, Camurus, and ITM; and personal fees from Exelixis, Harpoon Tx, Amryt Pharma, Ipsen, Lexicon, TerSera, Curium, AlphaMedix,, Crinetics, and Chimeric Therapeutics outside of the submitted work., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tintelnot et al. 1 identified enrichment of indole-3-acetic acid (3-IAA), a tryptophan metabolite produced by gut microbiota, as a predictor of chemotherapy response in pancreatic adenocarcinoma. Recapitulated in mouse models, 3-IAA represents a novel potential therapeutic approach for chemotherapy sensitization., Competing Interests: Declaration of interests J.A.W. is an inventor on a US patent application (PCT/US17/53.717); reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, MedImmune, and Bristol-Myers Squibb; serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals, and Micronoma. J.A.W. holds stock options from Micronoma., (Published by Elsevier Inc.)

Objective: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures., Design: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy., Results: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8 + T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function., Conclusion: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells., Competing Interests: Competing interests: VGP is a member of the scientific advisory board for TriSalus Life Sciences. He has served as a consultant for Merck & Company in 2018, GlaxoSmithKline in 2019, Imvax in 2019, Takeda in 2020 and Umoja in 2022. He has research funding from AstraZeneca, Ipsen, Merck, OncoResponse and NGM. The funders had no role in the conceptualisation, design, data collection, analysis, decision to publish or preparation of the manuscript. The anti-CEA CAR vector was provided by TNK Therapeutics, who had no role in the conceptualisation, design, data collection, analysis or preparation of the manuscript. SCK served as an advisor for TNK Therapeutics until December 2019, is currently Chief Medical Officer of TriSalus Life Sciences and SAB member of Nkarta, Takeda and Sentibio, and has received research funding from Takeda and Nkata., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite recent advances in the systemic treatment of gastrointestinal tumors, pancreatic adenocarcinoma (PDAC) remains a challenging disease, with 5-year survival just over 10%. Pancreatectomy in patients meeting defined anatomic criteria can result in cure; however, perioperative morbidity and mortality, as well as high rates of both local and distant recurrence even after "potentially curative" resection, have limited survival. Although perioperative chemotherapy has been shown to improve patients' longevity and chance for cure, debate continues about whether the preoperative or adjuvant approach is most effective in treatment of localized PDAC. Large, randomized multicenter trials in patients with resectable and borderline resectable PDAC have evaluated an evolving therapeutic landscape with mixed results. Importantly, these landmark studies share the fundamentally flawed assumption that tumor anatomical characteristics are an indicator of behavior and natural history. Concurrent biologic and translational research has revealed that rather than a single disease, PDAC represents a phenotypically variable group of malignancies arising in physiologically diverse patients. Ongoing novel trials have begun to capture this heterogeneity both in patient selection as well as the measurement of response by using genomic, transcriptional and radiomic markers. By moving away from classic anatomic descriptors to a more nuanced landscape of biomarkers predictive of tumor behavior and response, we can further refine the questions asked in preoperative trials and translate the answers to clinically meaningful precision therapy in localized PDAC., (© 2022 American Cancer Society.)

Purpose: To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design., Experimental Design: Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis., Results: All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy. The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and natural killer (NK) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant radiotherapy with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed postneoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathologic response (≥90% necrosis postneoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T-cell checkpoint TIM3 and downregulation of OX40 were observed posttreatment., Conclusions: Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for STSs., (©2022 American Association for Cancer Research.)

Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy., Competing Interests: Declaration of Competing Interest VGP: Laboratory research funding from Merck., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is the second most lethal malignancy globally and is increasing in incidence in the United States. Unfortunately, there are few effective systemic treatment options, particularly for disseminated disease. Glypican-3 (GPC3) is a proteoglycan cell surface receptor overexpressed in most HCCs and provides a unique target for molecular therapies. We have previously demonstrated that PET imaging using a 89 Zr-conjugated monoclonal anti-GPC3 antibody ( α GPC3) can bind to minute tumors and allow imaging with high sensitivity and specificity in an orthotopic xenograft mouse model of HCC and that serum alpha-fetoprotein (AFP) levels are highly correlated with tumor size in this model. In the present study, we conjugated 90 Y, a high-energy beta-particle-emitting radionuclide, to our α GPC3 antibody to develop a novel antibody-directed radiotherapeutic approach for HCC. Luciferase-expressing HepG2 human hepatoblastoma cells were orthotopically implanted in the livers of athymic nude mice, and tumor establishment was verified at 6 weeks after implantation by bioluminescent imaging and serum AFP concentration. Tumor burden by bioluminescence and serum AFP concentration was highly correlated in our model. Yttrium-90 was conjugated to α GPC3 using the chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and injected via the tail vein into the experimental mice at a dose of 200  μ Ci/mouse or 300  μ Ci/mouse. Control mice received DOTA- α GPC3 without radionuclide. At 30 days after a single dose of the radioimmunotherapy agent, mean serum AFP levels in control animals increased dramatically, while animals treated with 200  μ Ci only experienced a minor increase, indicating cessation of tumor growth, and animals treated with 300  μ Ci experienced a reduction in serum AFP concentration, indicating tumor shrinkage. Mean tumor-bearing liver weight in control animals was also significantly greater than that in animals that received either dose of 90 Y- α GPC3. These results were achieved without significant toxicity as measured by body condition scoring and body weight. The results of this preclinical pilot demonstrate that GPC3 can be used as a target for radioimmunotherapy in an orthotopic mouse model of HCC and may be a target of clinical significance, particularly for disseminated HCC., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2019 Andrew D. Ludwig et al.)

Although immunotherapy is currently being widely applied to treat a variety of cancers, there is great heterogeneity in the response to these treatments. Many in the field hypothesize that this may be attributable to the characteristics of each individual tumor immune microenvironment, in addition to systemic immune factors. Therefore, understanding the immune cell microenvironment in a variety of tumors is critically important. Specifically, the interactions among immune, stromal, and cancer cells, along with other factors in tumors, may hold the key to developing rational personalized combinations of immunotherapeutic drugs. We recently developed an organotypic slice culture technique, which enables precise study of the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment. We used a Vibratome to cut fresh human tumor tissue into 250 μm thick slices, and cultured slices on cell culture inserts with 0.4 μm pore to produce our tumor slice culture (TSC) system. We showed that TSC maintained many elements of the original tumor microenvironment and architecture for approximately one week. Using this slice culture technique for PDA, we demonstrated that immune cells, including T cells and macrophages, cancer cells, and stromal myofibroblasts were present throughout the culture period. TSCs were functionally responsive to drug treatment. Live PDA slices could be stained for multicolor immunofluorescence imaging of each of the primary cellular constituents of the tumor. Finally, autologous CFSE-labeled splenocytes were observed to readily migrate into cocultured tumor slices.

Background: Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited., Methods: The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vβ gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated., Results: UPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T-cell infiltration. UPS were found to have higher levels of PD-L1 (P≤.001) and PD-1 (P≤.05) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing, significantly more than SS, which had the lowest (P≤.05). T-cell infiltrates in UPS also were more oligoclonal compared with SS and liposarcoma (P≤.05). A model adjusted for STS histologic subtype found that for all sarcomas, T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels (P≤.01)., Conclusions: In the current study, the authors provide the most detailed overview of the immune microenvironment in sarcoma subtypes to date. UPS, which is a more highly mutated STS subtype, provokes a substantial immune response, suggesting that it may be well suited to treatment with immune checkpoint inhibitors. The SS and liposarcoma subsets are less mutated but do express immunogenic self-antigens, and therefore strategies to improve antigen presentation and T-cell infiltration may allow for successful immunotherapy in patients with these diagnoses. Cancer 2017;123:3291-304. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., (© 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease that is rarely cured, despite many recent successes with immunotherapy for other malignancies. As the human disease is heavily infiltrated by effector T cells, we postulated that accurately modeling the PDA immune microenvironment would allow us to study mechanisms of immunosuppression that could be overcome for therapeutic benefit. Using viable precision-cut slices from fresh PDA, we developed an organotypic culture system for this purpose. We confirmed that cultured slices maintain their baseline morphology, surface area, and microenvironment after at least 6 d in culture, and demonstrated slice survival by MTT assay and by immunohistochemistry staining with Ki-67 and cleaved-Caspase-3 antibodies. Immune cells, including T cells (CD3 + , CD8 + , and FOXP3 + ) and macrophages (CD68 + , CD163 + and HLA-DR + ), as well as stromal myofibroblasts (αSMA + ) were present throughout the culture period. Global profiling of the PDA proteome before and after 6 d slice culture indicated that the majority of the immunological proteins identified remain stable during the culture process. Cytotoxic effects of drug treatment (staurosporine, STS and cycloheximide, CHX) on PDA slices culture confirmed that this system can be used to assess functional response and cell survival following drug treatment in both a treatment time- and dose-dependent manner. Using multicolor immunofluorescence, we stained live slices for both cancer cells (EpCAM + ) and immune cells (CD11b + and CD8 + ). Finally, we confirmed that autologous CFSE-labeled splenocytes readily migrate into co-cultured tumor slices. Thus, our present study demonstrates the potential to use tumor slice cultures to study the immune microenvironment of PDA.

Robotic technology is being utilized in multiple hepatobiliary procedures, including hepatic resections. The benefits of minimally invasive surgical approaches have been well documented; however, there is some concern that robotic liver surgery may be prohibitively costly and therefore should be limited on this basis. A single-institution, retrospective cohort study was performed of robotic and open liver resections performed for benign and malignant pathologies. Clinical and cost outcomes were analyzed using adjusted generalized linear regression models. Clinical and cost data for 71 robotic (RH) and 88 open (OH) hepatectomies were analyzed. Operative time was significantly longer in the RH group (303 vs. 253 min; p = 0.004). Length of stay was more than 2 days shorter in the RH group (4.2 vs. 6.5 days; p < 0.001). RH perioperative costs were higher ($6026 vs. $5479; p = 0.047); however, postoperative costs were significantly lower, resulting in lower total hospital direct costs compared with OH controls ($14,754 vs. $18,998; p = 0.001). Robotic assistance is safe and effective while performing major and minor liver resections. Despite increased perioperative costs, overall RH direct costs are not greater than OH, the current standard of care.

Background: Esophageal perforation is an injury associated with high morbidity and mortality. Initial management ranges from observation to esophagectomy. The aim of this study was to evaluate the relative mortality and safety of emergent esophagectomy for acute esophageal rupture when compared with elective esophagectomies., Methods: We performed a retrospective review of a prospective esophagectomy database from a single institution from 1977 to 2013. Patients who were admitted for esophageal perforation and underwent esophagectomy were identified and compared with patients who underwent elective esophagectomy., Results: In all, 3,015 patients received an esophagectomy in elective and emergent settings; 90 esophagectomies were for acute injuries (52 for benign and 38 for malignant causes). A longer median length of stay was associated with emergent esophagectomy compared with elective esophagectomy (13 versus 10 days, p < 0.0001), and the complication rates were higher in the emergent group (51.1% versus 35.6%, p = 0.003). The survival rates at 30 days, 1 year, and 5 years after surgery were not significantly different between the emergent and nonemergent esophagectomy groups for patients with both benign and malignant underlying conditions. Within the emergent group, there was no difference in 30-day or 6-month survival based on benign or malignant causes, but a significant difference was seen at 1 year (85% for benign versus 65% for malignant, p = 0.025) and 5 years for survival (72% versus 21%, p < 0.001)., Conclusions: Emergent esophagectomy represents a safe option for the treatment of esophageal perforation, with mortality comparable to elective esophagectomy., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals.