Intraperitoneal Disease Research Articles

Indocyanine Green Fluorescence Guided Surgery in Colorectal Surgery.

Indocyanine green (ICG) imaging has been increasingly used for intraoperative guidance in colorectal surgery over the past decade. The aim of this study was to review and organize, according to different type of use, all available literature on ICG guided colorectal surgery and highlight areas in need of further research and discuss future perspectives. PubMed, Scopus, and Google Scholar databases were searched systematically through November 2022 for all available studies on fluorescence-guided surgery in colorectal surgery. Available studies described ICG use in colorectal surgery for perfusion assessment, ureteral and urethral assessment, lymphatic mapping, and hepatic and peritoneal metastases assessment. Although the level of evidence is low, results are promising, especially in the role of ICG in reducing anastomotic leaks. ICG imaging is a safe and relatively cheap imaging modality in colorectal surgery, especially for perfusion assessment. Work is underway regarding its use in lymphatic mapping, ureter identification, and the assessment of intraperitoneal metastatic disease.

Effect of Intraperitoneal 224Radium-Labelled Microparticles on Compartmentalized Inflammation After Cytoreductive Surgery and Hypertherm Intraperitoneal Chemotherapy.

Despite extensive treatment with surgery and chemotherapy many patients with peritoneal metastases from colorectal cancer experience intraperitoneal disease relapse. The α-emitting 224radium-labelled microparticle radionuclide therapeutic Radspherin® is being explored as a novel treatment option for these patients. Radspherin® is specially designed to give local radiation to the surface of the peritoneal cavity and potentially kill remaining attached micrometastases as well as free-floating cancer cells, thus preventing future relapse. The effect of Radspherin® on the immune system is not known. Systemic and local inflammatory responses were analyzed in plasma, intraperitoneal fluid and urine collected prospectively as part of a phase 1 dose-escalation study of intraperitoneal instillation of the α-emitting therapeutic radiopharmaceutical Radspherin®, at baseline and the first 7 postoperative days from nine patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. All patients additionally received intraperitoneal instillation of Radspherin® on postoperative day 2. Complement activation products C3bc and the terminal complement complex were analyzed using enzyme-linked immunosorbent assay. Cytokines (n = 27), including interleukins, chemokines, interferons and growth factors, were analyzed using multiplex technique. The time course and magnitude of the postoperative cytokine response after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy displayed a modest systemic response in plasma, in contrast to a substantial local intraperitoneal response. After administration of Radspherin®, a significant increase (P < 0.05) in TNF and MIP-1β was observed in both plasma and peritoneal fluid, whereas IL-9 increased only in plasma and IFNγ and IL1-RA only in peritoneal fluid. Only minor changes were seen for the majority of the inflammatory markers after Radspherin® administration. Our study showed a predominately local rather than systemic inflammatory response to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Radspherin® had overall modest impact on the inflammation.

S2366 Rare Case of 27-Year-Old With Esophageal Cancer

Introduction: Amongst esophageal cancers, neuroendocrine tumors represent 0.5 to 2.0% of cancers with a median age occurrence of 69 years old.1 Our case represents a 27-year-old patient with neuroendocrine esophageal cancer. Case Description/Methods: 27 year old female with history of obesity presented to clinic for acid reflux with globus sensation and stated symptoms are worse after eating. The patient started on famotidine 20mg daily with no improvement, patient developed dysphagia to solids daily. Esophagogastroduodenoscopy (EGD) demonstrated a 4cm mass at distal esophagus bridging the gastroesophageal junction with a 2cm cratered ulceration at the distal end of the mass. Computed tomography of the abdomen showed abdominal adenopathy and 11cm metastatic lesion at the liver as seen in Figure 1. Pathology was chromogranin A positive representing a neuroendocrine tumor. Patient started on carboplatin and VP-16. Currently, the patient continuing to receive chemotherapy and will receive PET scan within the next month. Discussion: As neuroendocrine tumors of the esophagus compromise a small portion of esophageal cancers with a female to male ratio of 1 to 3.7 emphasizing the importance of our case report.1 Clinical manifestations include weight loss, anemia, and dysphagia. Endoscopic biopsy will confirm biopsy. Visualization on biopsy provides guidance on staging; early esophageal cancer presents as superficial plaques, nodules or ulcerations. Advanced lesions will appear as strictures, ulcerated masses, circumferential mass, or a large ulceration. Regardless of visualization on endoscopy, diagnosis is confirmed by biopsy. Biopsy confirms with an endocrine marker, example chromogranin A, synaptophysin, and CD 56. Staging then assists in guiding treatment. Endoscopic ultrasound is one of the most accurate techniques to assess with locoregional staging. Most common sites of metastasis are liver, lungs, bones and adrenal glands. There is controversy regarding the use of diagnostic laparoscopy but procedure generally reserved for patients who have potentially resectable tumor, T3 or T4 staging, Siewert II or III adenocarcinomas of the esophageal gastroduodenal junction, or when there is a suspicion for an intraperitoneal metastatic disease that cannot be confirmed otherwise.Figure 1.: 1: large heterogeneous lesion within the right hepatic lobe, measuring 10.5 x 11.5 cm which appears to demonstrate central necrosis.REFERENCE 1. Egashira A, Morita M, Kumagai R, et al. Neuroendocrine carcinoma of the esophagus: Clinicopathological and immunohistochemical features of 14 cases. PLoS One 2017;12(3):e0173501.

Abstract 2553: Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes

Abstract High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, a high degree of tumor heterogeneity and intraperitoneal spread. As immunotherapies have thus far proven ineffective in this disease, we sought to establish the determinants of immune recognition, avoidance and evasion in disease natural history to gain insight into the co-evolutionary processes underlying malignant progression and host immunity. Accordingly we linked mutational processes and anatomic sites of tumor foci as determinants of tumor microenvironment (TME) cellular phenotypes within and between patients using genome-based stratification of homologous recombination proficient (HRP) and deficient (HRD) disease subtypes, and profiling single cell phenotypes from ~1 million cells including cancer cells, T cells, myeloid cells and fibroblasts derived from single cell RNA sequencing, and in situ spatial profiling of histopathology, cancer cell, T cell and macrophage states of 160 tumor sites obtained from 42 treatment-naive patients. Mutational processes in HRD-Dup (BRCA1 mutant-like) tumors were associated with cancer cell-intrinsic JAK/STAT signaling and predominance of highly-differentiated dysfunctional CD8+ T cells in the TME; HRD-Del (BRCA2 mutant-like) tumors were associated with cancer cell-intrinsic NF-κB and TNFα signaling and expansion of M2-type macrophages; and foldback inversion (FBI, HRP) tumors were associated with cancer cell-intrinsic TGFβ signaling and overall immune exclusion, with a predominance of naive/central memory-like T cells. Increased neoantigen burden and HLA loss of heterozygosity (LOH) were defining genomic features of the HRD, but not FBI tumors. These mechanisms of escape from immune predation, with distinct signalling activity and losses of HLA allelic diversity in HRD tumors, connect evolutionary selection with immunological phenotypic states. Multi-region sampling revealed substantial spatial variation, highlighting site-specific properties of the ovary and fallopian tube as putative “immune-privileged” sites. These results establish that in patients with widespread intraperitoneal disease, the local properties of organ sites may determine malignant cell selection and immune pruning. Furthermore, we observed that spatial cellular topology is a major determinant of tumor-immune interactions by in situ protein measurements, revealing ubiquitous PD1-PDL1 interactions in HRD tumors. Together, our findings yield mechanistic insights for how distinct mutational processes in HGSOC lead to diverse patterns of within- and between- patient variation in immune resistance, which can be exploited to optimize future immuno-therapeutic treatment strategies. Citation Format: Ignacio Vázquez-García, Florian Uhlitz, Nicholas Ceglia, Jamie L. Lim, Michelle Wu, Neeman Mohibullah, Arvin Eric B. Ruiz, Kevin M. Boehm, Viktoria Bojilova, Christopher J. Fong, Tyler Funnell, Diljot Grewal, Eliyahu Havasov, Samantha Leung, Arfath Pasha, Druv M. Patel, Maryam Pourmaleki, Nicole Rusk, Hongyu Shi, Rami Vanguri, Marc J. Williams, Allen W. Zhang, Vance Broach, Dennis S. Chi, Arnaud Da Cruz Paula, Ginger J. Gardner, Sarah H. Kim, Matthew Lennon, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Ritika Kundra, Agnes Viale, Yonina Bykov, Fatemeh N. Derakhshan, Luke Geneslaw, Ana Maroldi, Andrea Schietinger, Travis J. Hollmann, Samuel F. Bakhoum, Robert A. Soslow, Lora H. Ellenson, Nadeem Abu-Rustum, Carol Aghajanian, Claire F. Friedman, Andrew McPherson, Britta Weigelt, MSK SPECTRUM Consortium, Dmitriy Zamarin, Sohrab P. Shah. Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2553.

Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells

Deubiquitinases (DUBs) mediate the removal of ubiquitin from diverse proteins that participate in the regulation of cell survival, DNA damage repair, apoptosis and drug resistance. Previous studies have shown an association between activation of cell survival pathways and platinum-drug resistance in ovarian carcinoma cell lines. Among the strategies available to inhibit DUBs, curcumin derivatives appear promising, thus we hypothesized their use to enhance the efficacy of cisplatin in ovarian carcinoma preclinical models. The caffeic acid phenethyl ester (CAPE), inhibited ubiquitin-specific protease 8 (USP8), but not proteasomal DUBs in cell-free assays. When CAPE was combined with cisplatin in nine cell lines representative of various histotypes a synergistic effect was observed in TOV112D cells and in the cisplatin-resistant IGROV-1/Pt1 variant, both of endometrioid type and carrying mutant TP53. In the latter cells, persistent G1 accumulation upon combined treatment associated with p27kip1 protein levels was observed. The synergy was not dependent on apoptosis induction, and appeared to occur in cells with higher USP8 levels. In vivo antitumor activity studies supported the advantage of the combination of CAPE and cisplatin in the subcutaneous model of cisplatin-resistant IGROV-1/Pt1 ovarian carcinoma as well as CAPE activity on intraperitoneal disease. This study reveals the therapeutic potential of CAPE in cisplatin-resistant ovarian tumors as well as in tumors expressing USP8.

Splenic-preserving surgery in hydatid spleen: a single institutional experience.

Though hydatid disease affects many organs in the human body, splenic hydatid accounts for approximately 0.8-4% of all human echinococcosis cases. Up to recently, splenectomy was the preferred surgery for hydatid spleen. Since 1980, conservative options to treat such a disease have become more and more prevalent. Our study aimed to assess our experience in open splenic preservative surgery for splenic hydatid in a single institutional center. Our retrospective research included ten patients with splenic hydatid operated between August 2013 and January 2018 at our medical center. The spleen was affected alone in seven cases, the liver and spleen were affected in three cases, and one of the patients had intra-peritoneal cyst disease. The diagnosis was confirmed primarily by ultrasonography. In some instances, computed tomography and magnetic resonance imaging were required. A chest x-ray was performed to rule out pulmonary hydatid in all patients. Open surgery procedure, field isolation, cystic fluid aspiration, and injection of 1% cetrimide solution, respiration, endocystectomy, suture of cystic edges to the intracystic tube drain were performed. All surgeries had albendazole before and after the operation 15 mg/kg/day. There were no significant intra or postoperative complications, and no further surgery was required. Patients remained hospitalized for 3-5 days. No recurrence after 1-3 follow-up years. However, three patients failed to follow up within two years. Our experience with splenic hydatids prompts us to use splenic conservation surgery whenever possible instead of splenectomy.

Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.

Confocal Imaging of Single-Cell Signaling in Orthotopic Models of Ovarian Cancer.

Ovarian cancer (OVCA) is frequently detected at late stages of disease, often with dissemination throughout the peritoneal cavity surface, abdomen, and ascites fluid. Tumor signaling via mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways can promote OVCA progression and depend on local microenvironmental cues. To better study OVCA in situ within native tissue contexts, here we describe confocal microscopy techniques to image mouse models of intraperitoneal disease at a single-cell resolution. As a proof of principle demonstration, examples are highlighted for simultaneously imaging tumor vascularization, infiltrating and often immunosuppressive immune cells (tumor-associated macrophages), and OVCA kinase activity.

Impact of hysteroscopy on course of disease in high-risk endometrial carcinoma

ObjectivePrevious studies have investigated the impact of preoperative hysteroscopy on the staging and survival of predominantly grade 1 endometrial cancers. We sought to evaluate the effect of hysteroscopy on the...

HIPEC in advanced epithelial ovarian cancer: why is there controversy?

The randomized OVHIPEC study provided further evidence that adding heated intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery significantly improved recurrence-free and overall survival in stage III epithelial ovarian cancer (EOC) patients, who were ineligible for primary cytoreductive surgery due to extensive intraperitoneal disease. Because opinions have been divided as to whether HIPEC is now a new standard of care for advanced EOC, the pros and cons of this approach are examined. A comparison with the ongoing discussion about the role of intraperitoneal chemotherapy is made. For both techniques, experience is crucial and a learning curve essential. Compared with intraperitoneal chemotherapy, intraoperative application of HIPEC provides superior distribution through the peritoneal cavity. HIPEC, as given in OVHIPEC, did not significantly increase adverse events, had no negative effect on quality of life and was cost-effective. Despite the ongoing debate about HIPEC, an important first step in attempting to demonstrate the efficacy of HIPEC in the first-line setting has been made with OVHIPEC. Critics have been of value to optimize future trials with HIPEC in patients with EOC.

Primary cytoreductive surgery with or without Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for FIGO stage III epithelial ovarian cancer: The OVHIPEC-2 trial in progress.

TPS6100 Background: The addition of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) to interval cytoreductive surgery improves recurrence-free and overall survival in patients with FIGO stage III ovarian cancer who are ineligible for primary cytoreductive surgery due to extensive intraperitoneal disease. The effect of HIPEC remains undetermined in patients who are eligible for primary cytoreductive surgery. We hypothesize that the addition of HIPEC to a complete or near-complete (residual disease ≤2.5 mm) primary cytoreductive surgery improves overall survival in patients with FIGO stage III ovarian cancer. Methods: This international, randomized, open-label, phase III trial enrolls patients with newly diagnosed, histological proven FIGO stage III epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients with resectable umbilical, spleen or local bowel lesions may be included. Following complete or near-complete primary cytoreduction, patients are intra-operatively randomized (1:1) to receive HIPEC or no HIPEC. Patients in both study arms will receive six courses of adjuvant carboplatin-paclitaxel and maintenance PARP-inhibitor or bevacizumab according to current guidelines. The primary endpoint is overall survival. To detect a Hazard Ratio of 0.67 in favor of HIPEC, 200 overall survival events are required. Assuming that accrual will be completed in 60 months, and 12 months additional follow-up, 538 patients need to be randomized. All randomized patients will be included in the analysis for overall survival according to the intention to treat principle. Pre-specified subgroup analyses will be performed based on stratification factors (peritoneal cancer index at start of surgery, completeness of surgery), histologic subtype (high-grade serous versus other), and BRCA mutation (BRCA1/2 mutation versus wildtype). Secondary endpoints are recurrence-free survival, time to first subsequent anticancer treatment, and treatment related complications and toxicity. Exploratory endpoints are time to second subsequent anticancer treatment, health-related quality of life, and cost-effectiveness. The Institutional Review Board of the Netherlands Cancer Institute approved the trial, which is actively enrolling patients since January 2020. Clinical trial information: NCT03772028.

Abstract 2317: Dose control of CAR-like T cell activity through post-translational covalent loading of ligands to a universal immune receptor

Abstract The use of chimeric antigen receptor (CAR) T cells for the treatment of CD19+ hematologic malignancies has shown great success in the clinic, leading to FDA approval for various forms of leukemia. However, their broad use is limited since a CAR targets a single tumor associated antigen (TAA), which is not effective against tumors with heterogeneous TAA expression or emerging antigen loss variants. Further, stably engineered CAR T cells can continually proliferate and activate in response to antigen, potentially causing fatal cytokine release syndrome (CRS) or neurotoxicity without a means of quantifiable control. These toxicities and limitations have prompted the development of an alternative CAR format called universal immune receptors (UIRs). UIRs allow multi-antigen targeting with a single receptor to prevent and address antigen escape due to heterogeneity and loss, targeting ligand (TL) dose dependent control of CAR activity, control of CRS, and normal B cell reconstitution following CD19 targeting. However, all current formats rely on non-covalent engagement of the TL which can lead to issues with sub-optimal affinity and specificity. We have developed a next generation UIR system that allows for post-translational covalent attachment of TLs to the receptor. This is accomplished through the use of the SpyCatcher-SpyTag protein system. When combined at physiologic pH and temperature, these two proteins form a covalent bond. The SpyCatcher immune receptor (Spy-IR) contains the SpyCatcher protein as its extracellular domain attached to standard second-generation CAR intracellular signaling domains. Addition of TAA-specific TLs labeled with SpyTag allows for on-demand CAR generation through covalent bond formation between the TL and the receptor at the T cell surface. Here, primary human T cells expressing the Spy-IR are quantitatively loaded with targeting ligands, allowing for dose-titratable control of redirected T cell effector function and tumor cell lysis. Even as a single cell product, Spy-IR T cells can recognize an array of tumor antigens, (e.g. Her2, EGFR, EpCAM, and CD20) either simultaneously or sequentially to address the evolving tumor antigen landscape. Further, dose-dependent arming of Spy-IR T cells with TL allows for controlled immune recognition of cells expressing either high or low level antigen to distinguish between tumor and normal cells, thus providing an additional means of safety. Finally, preclinical efficacy of the Spy-IR system was achieved in NSG mouse models of aggressive solid tumor and intraperitoneal disease. In conclusion, the SpyCatcher immune receptor is the first UIR designed for post-translational covalent attachment of targeting ligands that permits timed “on demand” redirection of T cells against a diverse array of antigens, to address limitations of safety and antigen diversity by conventional CAR T cell therapy. Citation Format: Nicholas G. Minutolo, Prannda Sharma, Andrew Tsourkas, Daniel J. Powell. Dose control of CAR-like T cell activity through post-translational covalent loading of ligands to a universal immune receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2317.

Abstract 1950: Differential expression of MUC16 mucin (CA125) depending on the architecture of the tumors developed in an orthotopic mouse model of high-grade serous ovarian cancer

Abstract The histopathology of high-grade serous ovarian cancer (HGSOC) in orthotopic mouse models has received limited attention. Using immunosuppressed mice, we generated intraperitoneal HGSOC disease that includes formation of ascites and/or pleural effusions, together with a myriad of intra-abdominal growths. We studied 3 HGSOC cell lines evolved from the same patient along disease progression—a platinum-sensitive, PEO1; a platinum-resistant after further relapse, PEO4; and another at the end of life, PEO6. We found that the animals were prone to develop the disease sooner when implanted with cells obtained from the most advanced disease. Using these models, we characterized the histopathology of the masses preferably developed in the stomach-spleen-pancreas region enclosing the omentum. Other sites of tumor formation we found where the lower pelvic cavity, the peritoneal wall, the liver base, the diaphragm, the lungs, the uterus, and the ovaries. The architecture of the tumors was more often represented by slit-like fenestrations, yet certain zones displayed papillary, glandular, or solid structures sometimes including infiltrating lymphocytes. When we studied the expression of antigen CA125, we found that its pattern of staining was highly heterogeneous. In PEO1/4/6 cells maintained in culture CA125 was expressed in all cell types, yet with a major abundance aligned with disease evolution. In vivo, within the tumors, the expression of CA125 was mostly limited to the apical region of cells facing slit-like spaces generated in between solid sheets of tumor cells surrounded by fibrovascular stroma. When tumor cells were located deep within homogeneous solid masses devoid of slit-like fenestrations, they usually did not express CA125. In contrast, when cells were found gathered as multicellular structures free-floating in open spaces surrounding target organs—e.g. within the bursa around the ovaries—CA125 was highly expressed. This is coincident with the high expression of CA125 observed in vitro in cells spontaneously forming multicellular aggregates in suspension. It is likely that HGSOC cells express CA125 to face or invade into open spaces. In summary, this work reveals tissue heterogeneity and polarity in the expression of CA125 in solid tumors of HGSOC developed in immunosuppressed mice. This selected pattern of expression may be related to the oncogenic functions of CA125 (a.k.a. MUC16, a glycoprotein), such as protecting cells from immunological attacks, or promoting metastases by binding to mesothelin produced by mesothelial cells that line the peritoneal cavity. Citation Format: Alicia A. Goyeneche, Michael A. Lisio, Zu-hua Gao, Carlos M. Telleria. Differential expression of MUC16 mucin (CA125) depending on the architecture of the tumors developed in an orthotopic mouse model of high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1950.

Factors that influence survival in high-grade serous ovarian cancer: A complex relationship between molecular subtype, disease dissemination, and operability

Objectives: To investigate the relationship between molecular subtype, intraperitoneal (IP) disease dissemination patterns, resectability, and overall survival (OS) in advanced high-grade serous ovarian cancer (HGSOC).

CD49d (high) T cells in the ovarian cancer microenvironment are a potential target for the optimization of immune checkpoint therapy in ovarian cancer.

e17075 Background: Despite the correlation between tumor infiltrating lymphocytes and long-term survival, immune-based therapies have underperformed for the treatment of ovarian cancer. This is attributed to an immune suppressive intraperitoneal microenvironment. With evidence that T cell dysfunction in the ovarian tumor environment is not reflected peripherally, we hypothesized that anatomically restricted T cell subsets play a role in local disease regulation. High expression of integrin α4 (CD49d) is selectively seen on peritoneal T cells in patients and healthy mice. Here we tested whether CD49d(high) CD8 T cells also contribute to anti-tumor immunity in ovarian cancer models. Methods: Using a syngeneic immune competent model of high grade serous ovarian cancer (ID8ova), we evaluated the phenotype of CD49d(high) T cells at varying stages of intraperitoneal disease by flow cytometry. Antigen specificity was tested using a SIINFEKL/H-2Kb NIH tetramer assay. Results: CD49d is highly expressed by peritoneal CD8 T cells but not by splenocytes in tumor-bearing mice (29.8% vs. 3.3% of CD8 cells respectively). Supporting a role in anti-tumor immunity, 92% of tumor antigen-specific CD8 T cells in the peritoneal cavity expressed high CD49d. While the proportion of peritoneal CD8 cells that express high CD49d is similar in healthy and tumor-bearing mice, CD49d(high)CD8 cells upregulate the expression of co-inhibitory receptors with tumor progression. At late stages of the disease, PD-1, TIM3, and LAG3 are exclusively expressed by peritoneal CD49d(high) cells (range 94.7 +/- 3.05%). Consistent with our prior data, PD1+TIM3+LAG3+ CD8 T cells were not present in the spleen, confirming the anatomic specificity of this lymphocyte subset. Conclusions: These findings add to the accumulating evidence that tumor immunity is locally regulated and identify an IP specific subset of CD8 T cells that could be selectively targeted with immune checkpoint blockade. We predict that strategies directing immune therapy to the peritoneal tumor microenvironment will enhance treatment efficacy and limit off-target toxicities in women with ovarian cancer.

Prognostic impact of initial tumor load and intraperitoneal disease dissemination patterns in patients with advanced ovarian cancer undergoing complete cytoreductive surgery

IntroductionComplete removal of disease is the most important prognostic factor for patients with advanced epithelial ovarian carcinoma. However, the influence of carcinomatosis distribution on prognosis is unknown and the prognostic impact of implant size according to their location is poorly studied. Our objective was to assess the impact of peritoneal carcinomatosis quantitative and qualitative localizations on progression free survival (PFS) in patients with advanced epithelial ovarian carcinoma (AEOC) after complete cytoreductive surgery. MethodsWe conducted a monocentric cohort study, retrospective from October 2001 to July 2014. Inclusion criteria were high-grade AEOC patients without residual disease (CC0) after primary debulking surgery (PDS) or after interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT). Peritoneal carcinomatosis was assessed according to qualitative criteria and quantitative criteria. ResultsOne hundred and one patients were included. Median PFS was 21·2 months and median OS was 62·2 months. On the whole population, involvement of adipocytes-enriched areas tended to be associated with a decreased PFS and was significantly associated with a decreased OS. Any localization was associated with PFS or OS in the “IDS” subgroup. In the “PDS” subgroup, PCI score and involvement of the right mesocolic area were associated with a decreased PFS. ConclusionInitial tumor load has not been found associated with PFS after complete surgery. Adipocytes-enriched areas and right mesocolic areas involvement were associated with poor prognosis in patients receiving primary debulking surgery. Larger-scale studies are needed to assess whether initial tumor load has a prognostic impact even after complete cytoreductive surgery is achieved.

Should mucosal bowel invasion in ovarian cancer be assigned to FIGO stage IV disease?

ObjectivesThe FIGO staging consensus agreement from 2012 indicates that bowel mucosal invasion for epithelial ovarian cancer (EOC) should be assigned to stage IV disease. Finding no evidence justifying this recommendation, we examined the impact of recto-sigmoid colonic invasion on survival based on depth of invasion. MethodsPatients having recto-sigmoid resection to achieve complete gross resection for stage IIIC/IV EOC between 2003 and 2011 were included. For this study, mucosal invasion alone was not considered as stage IV. Degree of bowel invasion was defined as: serosal/subserosal vs. muscularis/submucosa/mucosa. Patients with only mesenteric invasion were excluded. Intraperitoneal disease (IP) dissemination patterns were defined as pelvic, lower abdomen, upper abdomen, and miliary disease. Comparisons between groups were evaluated using the log-rank test for progression-free and overall survival (PFS, OS) and the chi-square test for IP dissemination pattern. ResultsEighty-five patients were included with a mean age of 64.5 years. Most cases were serous (87.1%) and stage IIIC (83.5%). There were 53 (62.4%) patients with serosal/subserosal and 32 (37.6%) with muscularis/submucosa/mucosa invasion. Although not statistically significant, PFS and OS both favored cases with deeper invasion (muscularis/submucosa/mucosa vs. serosal/subserosal invasion: median PFS, 33.5 vs. 18.2 months, p = 0.34; median OS, 82.3 vs. 51.5 months, p = 0.46). When comparing patterns of disease dissemination, we observed that patients with serosal/subserosal invasion (vs. those with deeper invasion) tended to have more upper abdominal or miliary disease (67.9% vs. 48.4%, p = 0.08). ConclusionsDepth of recto-sigmoid colon wall invasion does not have prognostic significance. Our observations do not support assignment to a higher FIGO stage (IV) based solely on this factor.

Revised management of advanced primary colon cancer: Case series of 2 patients

BackgroundThe resection of a primary colon cancer has the opportunity to cure the patient of cancer by complete clearance and absolute containment of disease. Alternatively, if the cancer resection does not provide clearance and containment it will eventuate in local recurrence and peritoneal dissemination. MethodsCulpability of recurrence of colorectal cancer is difficult to determine. Are the management strategies of the primary cancer evaluation and treatment at fault or is the underlying disease process is to be held responsible? The clinical and radiologic findings that could have been evaluated by a multidisciplinary team (MDT) were critically evaluated in 2 patients with right colon adenocarcinoma. Strategies to accomplish complete clearance and absolute containment of the primary malignancy as resectable for cure were suggested. ResultsClinical evaluation of these 2 patients suggested that more knowledgeable preoperative evaluation by the multidisciplinary team (MDT) should have placed them in a high risk group for local recurrence and/or peritoneal dissemination. High carcinoembryonic antigen (CEA) tumor marker and by CT a large primary cancer infiltrating adjacent structures can be used to select advanced pre- and intraoperative treatment strategies. ConclusionsTwo patients who had an approximately 50% possibility of long-term survival with optimal preoperative evaluation and expert surgical resection techniques may have been converted to a greatly reduced survival because of tumor dissemination and positive margins of resection at the time of primary cancer resection. Neither patient was evaluated by an MDT preoperatively. It is possible that these two patients entered the operating room with a contained malignancy but as result of suboptimal pre- and intraoperative management left the operating room with disseminated intraperitoneal disease.

Xanthogranulomatous cholecystitis: pseudo tumor of gall bladder

Introduction: Xanthogranulomatous cholecystitis is an uncommon inflammatory disease of gall bladder with reported prevalence of 0.7% in US and 10% in India and Japan. Its final diagnosis can be made only after malignancy is ruled out on histopathological examination of resected gall bladder. Case presentation: 60 years female presented with complaints of pain in right upper abdomen, loss of appetite for 3 months. Physical examination was normal. Abdominal examination revealed tenderness in right upper quadrant and a hard, non tender globular mass suggestive of gall bladder lumpBlood parameters were normal. Contrast enhanced CT scan abdomen reported grossly distended gall bladder with 12 mm calculus at neck, pericholecystic fat stranding, asymmetric wall thickening and few lymph nodes. Serum CA19.9 -103 IU/l.. Diagnostic laparoscopy that ruled out intraperitoneal disease followed by cholecystectomy and wedge resection of liver. Intraoperatively, gall bladder was found to be hard, elongated, densely adhered to GB fossa with multiple calculi in it. Histopathologically greyish-yellow streaks in the gallbladder wall, transmural inflammation with dense lymphoplasmacytic infiltration and fibrosis, perineural plasma infiltrate, one of the areas showing storiform fibrosis, suggesting xanthogranulomatous or IgG4 cholecystitis. No malignancy present. Serum IgG levels were raised but IgG4 levels were normal. Immunohistochemistry for IgG4 plasma cells in the specimen was negative. Conclusion: Xanthogranulomatous cholecystitis is a perfect mimicker of carcinoma gall bladder and diagnosis is difficult, both pre and intraoperatively. It is a differential for IgG4 cholecystitis also which though rare isolated entity, is usually a part of spectrum of IgG4 related sclerosing diseases.

The pathologic distinction of primary and metastatic mucinous tumors involving the ovary: A re-evaluation of algorithms based on gross features

The problems associated with the pathologic distinction of primary ovarian mucinous tumors from their metastatic counterparts are well-recognized. Herein, we systematically evaluate a variety of gross parameters to determine the combination of features that most optimally separate primary from secondary mucinous ovarian tumors, and to address the tumor types that are most frequently associated with exceptions. 129 consecutive mucinous tumors involving the ovary formed the study set, including 61 primary mucinous tumors (16 carcinomas, 45 borderline tumors), and 68 metastatic carcinomas (21 colon; 28 appendix; 5 breast; 3 lung; 3 pancreas; 3 cervix; 1 bladder; 4 stomach). Consistent with prior studies, we found that as compared with metastases, primary ovarian mucinous tumors tend to be larger, more frequently unilateral and were more likely to be predominantly cystic and devoid of surface nodules. 41 of the 68 cases in the metastatic group showed intraperitoneal disease, as compared with only 3 of the 61 cases in the primary group (p < 0.0001). In 21% (14/68) of the metastatic group, the ovarian tumor was the first clinical indication of the primary tumor, and 82% of those cases were of gastrointestinal tract primary; this group of cases showed significantly larger tumors than ovarian tumors for patients with an established diagnosis of cancer. Receiver operating curve analyses showed that a tumor size cut off of <13 cm for metastatic disease yielded the maximal area under the curve of 0.877 (sensitivity 80%; specificity 80%); the most frequent exception to the size cut off of <13 cm for metastases was colorectal carcinoma, 30% of which were ≥13 cm. An algorithm whereby a tumor ≥13 cm is considered primary unless it displays surface nodules or bilaterality, and a tumor <13 cm is considered metastatic unless it is unilateral, correctly classified 94% (64/68) of the metastatic tumors and 98% (60/61) of the primary tumors. 3 of the 4 incorrectly classified cases in the metastatic group had intraperitoneal disease. We conclude that gross features are very useful in the distinction of primary from metastatic mucinous tumors in the ovary, and the presence of intraperitoneal disease provides additional diagnostic information. Although algorithms such as the one described herein are imperfect classifiers, they do provide baseline information on which additional findings, including microscopic features, can be added to ultimately provide the most accurate diagnostic classification.