Complete Tumor Clearance Research Articles

Endobronchial Hamartoma: A Rare Cause of Chronic Cough

A 57-year-old man with a 37-pack year history of smoking was referred to the pulmonary clinic for evaluation of chronic cough, shortness of breath, and intermittent episodes of right-sided chest pain of 6 months' duration. He reported a history of cocaine and heroin abuse, which he had quit 11 years before, and denied any other medical problems. Physical examination did not reveal any abnormalities. Computed tomography of chest revealed an endobronchial nodule in the right upper lobe (Panel A). Bronchoscopy revealed a smooth mass occluding the entrance of the right upper lobe bronchus (Panel B). Biopsies followed by argon plasma coagulation for tumor destruction was performed. Histopathology revealed epithelial and mesenchymal components consistent with hamartoma (Supplemental Image, Panel C, available online at http://www.mayoclinicproceedings.org). On follow-up 2 months later; the patient is doing well without respiratory limitations, with repeat bronchoscopy showing almost complete resolution (Supplemental Image, Panel D). Hamartomas are the most common benign tumors of the lung; however, the majority of these tumors are found peripherally, with an endobronchial location reported in 1.4% to 10% of cases.1Ahmed S. Arshad A. Mador M.J. Endobronchial hamartoma; a rare structural cause of chronic cough.Respir Med Case Rep. 2017; 22: 224-227Crossref PubMed Scopus (11) Google Scholar Download .pdf (3.67 MB) Help with pdf files Supplemental Image, Panel CHistopathology sections showing cartilage and adipose tissue, with respiratory epithelium consistent with hamartoma. Download .pdf (1.24 MB) Help with pdf files Supplemental Image, Panel DFollow up bronchoscopy showing almost complete clearance of tumor. Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

The role of ALPPS in intrahepatic cholangiocarcinoma.

Surgical resection constitutes the mainstay of curative treatment for intrahepatic cholangiocarcinoma (iCCA). Complete tumor clearance can only be achieved with extended liver resections and as such, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may facilitate surgical resectability. The present study aims to evaluate the technical feasibility and oncologic outcome of ALPPS in iCCA. A set of 14 patients who underwent ALPPS in a single center between 2011 and 2017 were statistically analyzed for perioperative and oncologic outcome. Of all patients undergoing stage 1 of ALPPS, 12 (86%) patients were subsequently completed in stage 2 surgery. Patients who completed the ALPPS procedure showed a median overall survival (OS) of 4.2 years and a 3-year survival of 64%. Individuals without lymphatic metastases (n = 7) were all alive 1 year after surgery and if deceased, they died more than 4 years after surgery, while no patient with lymphatic metastases (n = 5) was alive 1 year after surgery. This is the largest single-center experience of ALPPS in iCCA currently available in the literature showing excellent technical feasibility and encouraging overall survival in these patients.

Achieving Type C2 (Type III) Laparoscopic Radical Hysterectomy with Preservation of Nerves: A Possibility

Video Objective This video is a demonstration of nerve sparing radical hysterectomy done laparoscopically but what makes it unique is that we could achieve complete parametrectomy which is the most vital step to prevent pelvic recurrences. As we know, the lymphatics follow the veins, removal of parametrium and paracervix on both the sides becomes crucial in achieving complete tumor clearance. Preservation of the nerves helps in the maintenance of bladder, anorectal and sexual functions making the postoperative period better, less morbid & uneventful. In contrast to open surgery, where you have to palpate the tissues to know the extent of dissection of the parametrium, laparoscopy helps us to have an extra edge with pelvic anatomy and magnification of the same. Setting A 70 year old post-menopausal lady had presented to us with white P/V discharge and post-menopausal spotting. Cervical biopsy reported well differentiated squamous cell carcinoma and imaging revealed that there was no extension into the parametrium. Interventions This video highlights the efforts made for hemostasis during the procedure and the relationship of ureters with the uterine vessels on either side. Following the dictum, “fat belongs to the bladder” and “fat belongs to the rectum” that we have always followed, we achieve a bloodless field with preservation of the innervation to bladder and rectum on both the sides. Post-operative course of the patient was unremarkable and she didn't have any bowel and bladder complaints. Conclusion With proficient surgeons, we can achieve complete parametrectomy, equal survival rates and less pelvic recurrences in comparison to open surgery in a rebut to the LACC trial which has taken the world by a storm. It is all about the anatomy and the anatomy of parametrium is the key to achieve a laparoscopic nerve sparing radical hysterectomy with no local recurrences and no lifestyle changes postoperatively.

Abstract 3270: Mechanism of action of a novel agonist TNFR2 antibody that induces co-stimulation of T cells and promotes robust anti-tumor immunity

Abstract TNFR2 is a member of the TNF receptor superfamily that is upregulated upon T cell activation and is highly expressed by tumor-infiltrating effector and regulatory T cells. We investigated TNFR2 levels on T cells in syngeneic mouse tumor models and in secondary lymphoid tissues by flow cytometry. Non-regulatory T cells in the spleen and lymph nodes expressed little TNFR2 whereas Tregs constitutively expressed intermediate levels. In contrast, tumor-infiltrating effector T cells expressed high levels of TNFR2 with Tregs expressing the highest levels. To investigate TNFR2 as a therapeutic target, we generated a novel monoclonal antibody specific to murine TNFR2 and investigated its mechanism of action. Antibodies against murine TNFR2 were generated by screening a human antibody-display library or by rabbit immunization. Antibodies were assessed for affinity, ability to compete with TNFα and for developability. A select number of antibodies were expressed as murine IgG2a and evaluated for activity in multiple syngeneic mouse tumor models. The mechanism of action of the most active clone, Y9, was investigated further. In vitro, Y9 stimulation of purified T cells from healthy mice caused increased proliferation and effector function, indicating that Y9 acts as an agonist and can provide co-stimulation. In vivo, Y9 treatment of mice with established tumors resulted in complete tumor clearance across a variety of models. Using CRISPR knockout cell lines, we showed that Y9 activity did not depend on TNFR2 expression on tumor cells. However, it required T cells as it showed no activity in nude mice. The activity of Y9 on immune cells was further confirmed by its decreased activity in mice depleted of NK or CD8+ T cells. Unlike the proposed Treg-depletion mechanism for other co-stimulatory therapeutic antibodies, depletion of Tregs is not the primary mechanism of action of Y9 treatment. Instead, decreased TNFR2 and other co-inhibitory receptor surface expression was observed following treatment. Y9 activity depended on FcγR binding as demonstrated by the lack of activity of an antibody variant with mutations preventing FcγR binding. We showed further that FcγR binding facilitated enhanced agonist activity by comparing activity of Y9 variants with different Fc isotypes and in FcγR knockout mice. We present a novel anti-TNFR2 antibody that exhibited pronounced anti-tumor in vivo activity in our mouse models with co-stimulation of tumor-specific T cells as its dominant mechanism of action. A corresponding human anti-TNFR2 antibody (MM-401) has been identified and is being developed as a potential novel treatment option for cancer patients. Citation Format: Ross B. Fulton, Adam Camblin, James F. Sampson, Jennifer Richards, Christina Wong, Alexander Koshkaryev, Lia Luus, Yang Jiao, Lihui Xu, Violette Paragas, Maja Razlog, Marco Muda, Eric M. Tam, Daryl C. Drummond, Andreas Raue. Mechanism of action of a novel agonist TNFR2 antibody that induces co-stimulation of T cells and promotes robust anti-tumor immunity [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 3270.

A novel TNFR2 antibody induces T cell co-stimulation and promotes durable anti-tumor immunity

Abstract TNFR2, an emerging therapeutic target in immuno-oncology, is upregulated upon T cell activation and is expressed by tumor-infiltrating effector and regulatory T (Treg) cells. We generated a novel monoclonal antibody, Y9, specific to murine TNFR2 and investigated its mechanism of action. In vitro, Y9 stimulation of purified T cells increased proliferation and effector function, indicating that Y9 acts as an agonist and can provide co-stimulation. In vivo, Y9 treatment of mice with established tumors resulted in complete tumor clearance across a variety of models. The activity of Y9 on immune cells was confirmed by its decreased activity in mice depleted of NK or CD8+ T cells. Unlike the proposed Treg depletion mechanism of other therapeutic antibodies, depletion of Treg cells is not the primary mechanism of action of Y9 treatment. Instead, decreased TNFR2 and other co-inhibitory receptor surface expression was observed following treatment. Y9 activity depended on FcγR binding, which facilitated enhanced agonist activity. Based on this evidence, we developed MM-401, a human antibody targeting TNFR2. MM-401 has agonistic activity; upon incubation of MM-401 with human CD4+ and CD8+ T cells, we observed upregulation of activation markers and cytokine production comparable to MEDI6469 (anti-OX40). We also observed that MM-401 promotes antibody-dependent cellular cytotoxicity (ADCC) in an NK cell-mediated in vitro assay and a reduction in the number of Treg cells in human ovarian cancer ascites. These data suggest that MM-401 could also promote anti-tumor immunity by mediating ADCC, as well as by direct co-stimulation of T cell responses, and justifies the continued development of MM-401 as a novel cancer immunotherapy.

RNA Viruses as Tools in Gene Therapy and Vaccine Development.

RNA viruses have been subjected to substantial engineering efforts to support gene therapy applications and vaccine development. Typically, retroviruses, lentiviruses, alphaviruses, flaviviruses rhabdoviruses, measles viruses, Newcastle disease viruses, and picornaviruses have been employed as expression vectors for treatment of various diseases including different types of cancers, hemophilia, and infectious diseases. Moreover, vaccination with viral vectors has evaluated immunogenicity against infectious agents and protection against challenges with pathogenic organisms. Several preclinical studies in animal models have confirmed both immune responses and protection against lethal challenges. Similarly, administration of RNA viral vectors in animals implanted with tumor xenografts resulted in tumor regression and prolonged survival, and in some cases complete tumor clearance. Based on preclinical results, clinical trials have been conducted to establish the safety of RNA virus delivery. Moreover, stem cell-based lentiviral therapy provided life-long production of factor VIII potentially generating a cure for hemophilia A. Several clinical trials on cancer patients have generated anti-tumor activity, prolonged survival, and even progression-free survival.

Abstract CT145: A Cancer Research UK phase I trial of anti-GD2 chimeric antigen receptor (CAR) transduced T-cells (1RG-CART) in patients with relapsed or refractory neuroblastoma

Abstract Background: Treatment of high risk neuroblastoma remains challenging; current multimodal treatment regimens achieve long term survival in <50% of patients and are associated with significant morbidity. Ganglioside GD2 is abundantly expressed on almost all neuroblastomas whilst expression on normal tissue is highly limited, providing a suitable CAR target. Here, we report the preliminary results of a Phase I clinical study of GD2-CART for refractory/relapsed neuroblastoma (NCT02761915). Trial design: The therapeutic (1RG-CART) is autologous T-cells transduced with a gamma-retroviral vector encoding both an anti-GD2 CAR and the RQR8 suicide gene. The CAR comprises a humanized anti-GD2 single chain variable fragment derived from the K666 antibody and CD28/CD3ζ signalling domains. Both lymphodepletion and CART dose were escalated as follows: dose level (DL) 1 without lymphodepletion, DL2 with 1.2 g/m2 cyclophosphamide and DL3 and beyond 1.2 g/m2 cyclophosphamide and 125 mg/m2 fludarabine followed by administration of a single intravenous dose of 1x107/m2 (DL1-3) or 1x108/m2 (DL4) 1RG-CART. Primary objectives are to assess safety and tolerability. Results: To date, 12 patients have been enrolled. All had relapsed/refractory neuroblastoma with measurable disease in bone (n=11), bone marrow (n=7) and/or soft tissue sites (n=9). Cell products were successfully manufactured for all patients. Median transduction efficiency was 34.5% (range 16-54%). Nine patients have been treated on DL1 (n=4), DL2 (n=1), DL3 (n=1) and DL4 (n=3) respectively. No dose limiting toxicity (DLT) was seen. For patients treated on DL1-3 (1x107/m2), 1RG-CART could not be detected in peripheral blood, and no clinical responses were seen. In contrast, expansion of 1RG-CART cells as detected by flow cytometry and qPCR was seen in the 3 patients treated on DL4 (1x108/m2). In two DL4 patients, 1RG-CART expansion was still limited and transient (marking levels <10,000 copies/μg DNA). These patients had disease progression as measured at Day +28. In one DL4 patient however, 1RG-CART marking levels of >40,000 copies/μg DNA were achieved. This patient developed Grade 2 cytokine release syndrome (Day +5) and biochemical evidence of tumour lysis (Day +21). Disease reassessment on Day +28 showed response in many sites of bone/marrow disease as measured by mIBG scintigraphy, and near complete tumour clearance in bone marrow which at baseline was heavily infiltrated with neuroblastoma. Disease progression occurred on Day +45 at which time 1RG-CART were no longer detectable. In the absence of DLT this prompted us to continue with DL5 (1x109/m2). Conclusions: These preliminary results are the first to demonstrate on-target activity in bone and bone marrow of GD2-CART in this childhood solid tumour. Further 1RG-CART dose escalation is warranted, and under way. Citation Format: Karin Straathof, Barry Flutter, Rebecca Wallace, Simon Thomas, Gordon Cheung, Angela Collura, Talia Gileadi, Jack Barton, Gary Wright, Sarah Inglott, David Edwards, Claire Barton, Karen Dyer, Nigel Westwood, Thalia Loka, Sarita Depani, Karen Howe, Giuseppe Barone, Martin Pule, John Anderson. A Cancer Research UK phase I trial of anti-GD2 chimeric antigen receptor (CAR) transduced T-cells (1RG-CART) in patients with relapsed or refractory neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT145.

Myotarsal flap – a versatile entity for lower eyelid reconstructions

ABSTRACTThe purpose is to present a new surgical technique using myotarsal (MT) flap for reconstruction of small to subtotal full thickness defects - up to 8 mm in height - of lower eyelids, without needing concomitant supplementary procedures. MT flap consists of a 3 mm tarsal strip with attached levator complex. It does not have conjunctival lining or pedicle. Versatility of the flap extends to correction of mild to severe ptosis, and retraction of upper eyelids. This is a retrospective personal series of 163 patients, who underwent surgical reconstruction with MT flap overlaid with quilted skin graft (modified myotarsal flap) after excision of malignant tumours of lower eyelid. Surgery was on day case basis under LA. Patients were assessed for aesthetic and functional outcome, and complications. No patient had any complication. Assessment of outcome included corneal and ocular surface health and protection, eye closure, tear secretion, and lid contours. These were aesthetically and functionally satisfactory. Histology confirmed complete tumour clearance, and clinical diagnosis. There was no recurrence of tumour. An astounding, new, unique and original observation of the study is that cornea and ocular surface remained undamaged throughout, despite absence of conjunctival lining of MT flap. This goes against all current tenets of oculoplasty. Use of the modified MT flap is a safe, versatile, and effective procedure yielding satisfactory aesthetic and functional results for reconstruction of the lower eyelid.

An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma

AbstractB-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. “A proliferation-inducing ligand” (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI− and BCMA−TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.

Neoadjuvant therapy affects margins and margins affect all: perioperative and survival outcomes in resected pancreatic adenocarcinoma

BackgroundResection margin status is an important prognostic factor in pancreatic cancer; however, the impact of positive resection margins in those who received neoadjuvant therapy remains unclear. The current study investigates the prognostic impact of resection margin status after neoadjuvant therapy and pancreaticoduodenectomy for patients with pancreatic adenocarcinoma. MethodsPatients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma between 2006 and 2013 were identified from the National Cancer Database. Multivariable logistic regression analysis was utilized to examine the predictive value of neoadjuvant therapy for resection margin status. Long-term outcomes were compared using a Cox proportional hazards model. Results7917 patients were identified in total: 1077 (13.6%) and 6840 (86.4%) patients received neoadjuvant therapy and upfront surgery, respectively. Upfront surgery was independently predictive of a positive margin (25.7% vs. 17.7%; OR, 1.54) compared to neoadjuvant therapy. After receipt of neoadjuvant therapy, positive margins (median overall survival, 18.5 vs. 25.9 months; HR, 1.58) remained significantly associated with poor survival on multivariable analysis. DiscussionWhile neoadjuvant therapy is associated with decreased R1/R2-resection rates after pancreaticoduodenectomy, the poor prognostic impact of positive margins is not abrogated by neoadjuvant therapy, stressing the need for complete tumor clearance and postoperative treatment even after neoadjuvant therapy.

Soluble SLAMF6 Receptor Induces Strong CD8+ T-cell Effector Function and Improves Anti-Melanoma Activity In Vivo.

SLAMF6, a member of the SLAM (signaling lymphocyte activation molecules) family, is a homotypic-binding immune receptor expressed on NK, T, and B lymphocytes. Phosphorylation variance between T-cell subclones prompted us to explore its role in anti melanoma immunity. Using a 203-amino acid sequence of the human SLAMF6 (seSLAMF6) ectodomain, we found that seSLAMF6 reduced activation-induced cell death and had an antiapoptotic effect on tumor-infiltrating lymphocytes. CD8+ T cells costimulated with seSLAMF6 secreted more IFNγ and displayed augmented cytolytic activity. The systemic administration of seSLAMF6 to mice sustained adoptively transferred transgenic CD8+ T cells in comparable numbers to high doses of IL2. In a therapeutic model, lymphocytes activated by seSLAMF6 delayed tumor growth, and when further supported in vivo with seSLAMF6, induced complete tumor clearance. The ectodomain expedites the loss of phosphorylation on SLAMF6 that occurs in response to T-cell receptor triggering. Our findings suggest that seSLAMF6 is a costimulator that could be used in melanoma immunotherapy. Cancer Immunol Res; 6(2); 127-38. ©2018 AACR.

Abstract B14: A restricted cell population propagates MPNST growth after treatment

Abstract Malignant peripheral nerve sheath tumor is a type of soft-tissue sarcoma that arises from the neural crest lineage and is commonly associated with nerve trunks. Surgical removal is the major treatment conjugated with chemo/radiation therapy when applicable. However, the complete tumor clearance is limited by the resectability, especially when tumor is associated with large peripheral nerve such as sciatic nerve, brachial plexus, and sacral plexus. The local recurrence of MPNST is 40-45% and distal recurrence is 40-48%. By harnessing our Nes-hsvTK-GFP transgene that successfully labeled the cancer stem cells in glioblastoma, we identified a small quiescent cell population in MPNSTs from both cisNf1+/-;Trp53+/- (cisNP) spontaneous model and skin progenitor (SKP)-based allograft model. Inhibition of these cells by feeding mice ganciclovir chow significantly decreased the tumor growth in both cisNP model and allograft model. We also found that the transgene-labeled GFP+ cells enrich in the sciatic nerve region compared to the distal tumor mass in MPNST allograft model. Tumor primary culture from the sciatic nerve vicinity forms significantly larger and more spheres in vitro than the distal tumor mass. The BrdU-EdU sequential labeling assay after chemotherapy in MPNST allograft model shows that the GFP+ cells can continuously repopulate tumor. These results indicate that the transgene-labeled GFP+ cells may serve as a source of tumor growth and, at the same time, a novel target to reduce MPNST relapse after treatment. Citation Format: Daochun Sun, Luis Parada. A restricted cell population propagates MPNST growth after treatment [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B14.

Multidisciplinary treatment of colorectal liver metastases.

The therapy of patients with colorectal liver metastases (CRLM) has undergone significant changes. Extended survival has been observed to be associated with adoption of hepatic resection and improved chemotherapy. This review summarizes standards, developments and controversies on the management of these patients. Literature search was performed with focus on work published within the last ten years. Patients with CRLM should undergo surgery whenever possible with careful and experienced patient selection as hepatic resection offers the best long-term prognosis. The multidisciplinary approach has markedly evolved and has increased the number of patients in whom curative-intended surgery is possible. Patients with resectable metastases can undergo upfront surgery or may receive perioperative chemotherapy in selected cases, a decision which is under debate and remains individual. Patients with non-resectable metastases that may become resectable upon conversion treatment should receive polychemotherapy with or without local ablative therapy as pretreatment with the main goal of achieving resectability. In patients with synchronous CRLM, the optimal sequence of treatment remains unclear. Depending on the hepatic tumor burden and its dynamics as well as the type and stage of the primary tumor, simultaneous resection or either the sequential "bowel-first" or reversed "liver-first" approach represent suitable options to achieve complete tumor clearance. The improvements in the management of CRLM due to multidisciplinary treatment and novel developments are a great example of successfully pushing the boundaries of cure in metastatic cancer. Surgery aiming at complete tumor clearance represents the central instrument to achieve long-term survival.

GITR ligand fusion protein agonist enhances the tumor antigen\u2013specific CD8 T-cell response and leads to long-lasting memory

BackgroundThe expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations.MethodsWe explored two separate murine tumor models, CT26 and TC-1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy. In TC-1, GITRL-FP was also combined with concurrent administration of an E7-SLP vaccine. We evaluated tumor growth inhibition by tumor volume measurements as well as changes in CD8 T cell populations and function including cytokine production using flow cytometry. Additionally, we interrogated how these therapies resulted in tumor antigen-specific responses using MHC-I dextramer staining and antigen-specific restimulations.ResultsIn this study, we demonstrate that a GITR ligand fusion protein (GITRL-FP) is an effective modulator of antigen-specific CD8 T cells. In a CT26 mouse tumor model, GITRL-FP promoted expansion of antigen-specific T cells, depletion of regulatory T cells (Tregs), and generation of long-lasting CD8 T cell memory. This memory expansion was dependent on the dose of GITRL-FP and resulted in complete tumor clearance and protection from tumor rechallenge. In contrast, in TC-1 tumor–bearing mice, GITRL-FP monotherapy could not prime an antigen-specific CD8 T cell response and was unable to deplete Tregs. However, when combined with a vaccine targeting E7, treatment with GITRL-FP resulted in an augmentation of the vaccine-induced antigen-specific CD8 T cells, the depletion of Tregs, and a potent antitumor immune response. In both model systems, GITR levels on antigen-specific CD8 T cells were higher than on all other CD8 T cells, and GITRL-FP interacted directly with primed antigen-specific CD8 T cells.ConclusionsWhen taken together, our results demonstrate that the delivery of GITRL-FP as a therapeutic can promote anti-tumor responses in the presence of tumor-specific CD8 T cells. These findings support further study into combination partners for GITRL-FP that may augment CD8 T-cell priming as well as provide hypotheses that can be tested in human clinical trials exploring GITR agonists including GITRL-FP.

Total Laparoscopic Resection Surgery for a Cervical Carcinoma that Recurred in the Pelvic Sidewall After Radical Hysterectomy and Adjuvant Concurrent Chemoradiotherapy

Study ObjectiveTo show total laparoscopic resection of a cervical carcinoma that recurred at the left pelvic sidewall after radical hysterectomy and concurrent chemoradiotherapy (CCRT). DesignA step-by-step demonstration of the technique in a surgical video, including the strategy for achieving complete surgical resection with negative margins (R0 resection) (Canadian Task Force Classification III). SettingFor high-risk cervical carcinoma, radical hysterectomy and adjuvant CCRT is the standard treatment, but even this multimodal therapy cannot prevent recurrence. When the recurrent mass is localized in the pelvic cavity, R0 resection offers the most promise; however, for laterally recurring cervical carcinoma, the resectability rate is low, owing mainly to severe adhesion and fibrosis, and thus the morbidity and mortality rates are high. Because laparoscopy optimizes visualization and provides for meticulous dissection, laparoscopic surgery can be advantageous over open surgery for resection of cervical carcinoma recurring at the pelvic sidewall after radical hysterectomy and adjuvant CCRT. InterventionsA 48-year-old woman with stage IB2 cervical adenocarcinoma had undergone radical hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and, because lymph node metastasis was found in the removed lymph nodes, adjuvant CCRT. At 6 months after completion of this multimodal therapy, a recurrent mass was detected at the left pelvic sidewall. The mass involved the left ureter, bladder, left internal iliac vessels, and endopelvic fascia, and left renal function was unrecoverable. Tumor excision and left nephroureterectomy were performed laparoscopically. The total operating time was 608 minutes, blood loss volume was 250 mL, and blood transfusion was not required. Complete tumor clearance (R0 resection) was achieved by resection of the left internal iliac vessels, left internal obturator muscle, left pubococcygeal muscle, left ureter, and bladder. There were no postoperative complications. Institutional Review Board approval was obtained through our local Ethics Committee in Cancer Institute hospital. ConclusionComplete laparoscopic resection surgery for recurrent cervical carcinoma at the pelvic sidewall after radical hysterectomy and adjuvant CCRT is technically feasible. The good visualization and meticulous dissection provided during laparoscopic surgery make the approach advantageous for the management of laterally recurrent cervical carcinoma.

Total laparoscopic pelvic exenteration for a laterally recurrent cervical carcinoma with a vesicovaginal fistula that developed after concurrent chemoradiotherapy

ObjectiveFor locally advanced cervical carcinoma, concurrent chemoradiotherapy (CCRT) is the standard treatment, however, CCRT can lead to development of a vesicovaginal or rectovaginal fistula [1]. Treatment options are limited for patients with laterally recurrent cervical carcinoma and fistula formation after CCRT. Chemotherapy with bevacizumab is now used for recurrent or advanced cervical carcinoma, but this treatment is associated with fistula formation [2]. When the recurrent mass is confined to the pelvic cavity, complete surgical resection with negative margins offers the most promise; however, the resectability rate is low in cases of laterally recurrent tumor [3], which may include bony structures, and survival outcomes seem to be poor in cases of a laterally recurrent vs. centrally recurrent tumor, even when the primary tumor has been resected in full [4]. Because analyses have shown that laparoscopy optimizes visualization and thus provides for meticulous dissection and that laparoscopic pelvic exenteration, in comparison to open pelvic exenteration results in minimal intraoperative blood loss and complications, fewer postoperative complications, and a shorter hospital stay [5], we perform laparoscopic pelvic exenteration in cases of laterally recurrent cervical carcinoma. MethodsA 52-year-old woman underwent CCRT for a 10-cm stage IVA cervical carcinoma. That involved the bladder and right ureter, causing right hydronephrosis. Seven months after the CCRT, a recurrent mass at the right pelvic sidewall and vesicovaginal fistula were detected. The mass involved the right ureter and bladder and was attached to the rectum. The patient's right renal function was lost. ResultsTotal pelvic exenteration and right nephroureterectomy were performed laparoscopically. Operation time was 566min, and the blood loss volume was 250mL. Complete tumor clearance was achieved without any complication. No adjuvant treatment has been performed, and follow-up positron emission tomography-computed tomography has revealed no sign of recurrence during the 5months that have passed since the surgery. ConclusionTotal laparoscopic pelvic exenteration is technically feasible for a laterally recurrent cervical carcinoma and vesicovaginal fistula that develop after CCRT.

Circulating tumor DNA analysis before and after resection for colorectal cancer.

3597 Background: Detection of circulating tumor DNA (ctDNA) has broad clinical utility including disease monitoring, prognostication and response to chemotherapy. ctDNA is commonly detected by targeting tumor-specific features including mutations, insertions, deletions or hypermethylation. The two genes, BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer (CRC). This study aimed to analyze the impact of tumor resection on ctDNA levels by assaying pre- and postoperative blood samples for methylated BCAT1 and IKZF1. Methods: 91 people (age 32-86 years, 53% male) with invasive CRC, but without neoadjuvant therapy, had blood collected prior to surgery and within 12 months (1-12 months) after resection. Cancers were clinicopathologically staged. DNA extracted from plasma was assayed for methylated BCAT1/ IKZF1 and detection of either marker was deemed positive for ctDNA. Results: 47 (52%) of the 91 CRC patients were ctDNA positive before resection, including 5/30 (17%) stage I, 17/28 (61%) stage II, 23/31 (74%) stage III and 2/2 (100%) stage IV. After resection 75% (35/47) became ctDNA negative (median 2 months after resection), and all had apparent tumour clearance. Of the 35 postoperative ctDNA negative cases 22 had further surveillance CT scans within study timeframe. 86% (20/22) showed no recurrent CRC but 2 of these developed a new cancer (metachronous CRC, prostate). The remaining 2 tested ctDNA positive 14 and 25 months later and recurrence was confirmed. Of the 12 postoperative ctDNA positive cases, two were found to not have complete tumour clearance at surgery (residual disease). Follow-up CT scans were available for a further 8 patients which revealed that 4 later presented with cancer (3 recurrence, 1 thyroid) at a median 15 months after resection. The remaining 4 postoperative positive cases were negative at subsequent blood testing (median 8 months later). Conclusions: Methylated BCAT1/IKZF1 DNA in preoperative blood is dependent on tumor stage, but informs the completeness of resection given the high rate (74.5%) of ctDNA disappearance post-surgery. If cases persistently test ctDNA positive after surgery or become ctDNA positive later, residual or recurrent disease should be suspected, respectively.

Surgery for Recurrent Uterine Cancer: Surgical Outcomes and Implications for Survival-A Case Series.

The purpose of this study was to describe the patterns of relapse in uterine cancer (UC) and the role of surgery in the recurrent setting. We describe surgical and clinical outcomes of all patients who underwent surgery for recurrent UC in a gynecological oncology tertiary referral center between May 1, 2013, and April 30, 2016. Progression-free survival and overall survival were estimated using Kaplan-Meier methods with the surgery at relapse being the starting point. We evaluated 15 patients with a median age of 66 years. The predominant histology was the endometrioid variant (n = 11; 73.3%). The median interval between the end of previous treatment and relapse surgery was 24 months (range, 8-164). Locoregional pelvic recurrences were the most common type of recurrence (n = 13; 86.7%) with the para-aortic lymph node space being the most commonly affected extrapelvic site (13%). Patients predominantly presented with a multifocal pattern of relapse (n = 10; 66.7%) requiring multivisceral resections such as bowel (n = 7; 46.6%) and/or bladder/ureteric resections (n = 8; 53.3%) to achieve complete tumor clearance. All patients were operated tumor free with a 30-day major morbidity and mortality rate of 6.7% and 0%, respectively. Five patients (33.3%) received postoperative chemotherapy or radiotherapy. Five patients (33.3%) relapsed, and 3 died within a mean follow-up of 12.4 months (95% confidence interval [CI], 6.5-18.2). Two of those patients had a sarcoma.Mean progression-free survival and overall survival for the entire cohort postrelapse surgery was 21.7 months (95%CI, 13.9-29.5) and 26.0 months (95%CI, 18.4-33.7), respectively. Survival was significantly worse in patients with nonendometrioid histology (P < 0.0001). Surgery for UC relapse seems feasible with acceptable morbidity and high complete resection rates despite the multifocal patterns of relapse in a selected group of patients in a reference center for gynecological cancers. Larger scale studies are warranted to establish the value of surgery at relapse for UC.

Liver surgery for metastatic colorectal cancer: the surgical oncologist perspective

Neoadjuvant/conversion chemotherapy has emerged as an indispensable tool to achieve resectability of initially unresectable metastatic colorectal cancer and improves oncological outcomes. In parallel, surgical strategy has adopted a more aggressive treatment approach to achieve complete tumor clearance. However, chemotherapy affects liver function and combined with extensive liver resection, morbidity has increased, thereby compromising oncological outcome. There is an imperative need for careful patient selection to optimize patient management. In this review, we discuss available evidence and indications for neoadjuvant treatment in the management of colorectal cancer liver metastases, on preoperative patient selection and identification of high-risk patients, potential treatment strategies to promote postoperative liver regeneration to avoid postoperative morbidity and potentially deleterious side effects of these therapies on tumor growth.

Application of indocyanine green near infrared fluorescence imaging in the surgical treatment of hepato-cellular carcinoma

Objective To investigate the clinical application of indocyanine green (ICG) near infrared fluorescence imaging in the surgical treatment of hepatocellular carcinoma (HCC). Method The prospective study was adopted. The clinicopathologic data of 24 patients with HCC who underwent surgical resection at the General Hospital of PLA from October 2014 to February 2015 were collected. Intravenous injection of ICG (0.5 mg/kg) was performed before surgery (range, 20.0-120.0 hours, mean, 47.5 hours). After free liver in open surgery, tumor lesions were displayed by fluorescent detector probe and completely resected under the guidance of the probe. The residual liver in vivo was detected, especially resection margin, and rapid frozen pathological examination of suspected lesions were conducted during operation. Fluorescence imaging of isolated tumor specimens was performed, the results of which were analyzed with results of pathological examination. Fluorescence imaging characteristics of the preoperative tumor, new lesions and isolated tumor specimens were observed. The follow-up using outpatient examination and telephone interview was performed for 1 year up to October 2015. The enhanced rescan of computed tomography (CT) and laboratory reexamination were performed every 3 months, and recurrence rate and mortality were recorded. Measurement data with normal distribution were represented as average (range). Result (1) Twenty-four primary lesions in 24 patients were detected by preoperative imaging examination. Of the 24 primary lesions, 19 showed fluoresce on the liver surface with an average depth of 0.36 cm (range, 0.00-0.65 cm) and an average diameter of 6.20 cm (range, 1.20-9.00 cm), 5 didn't show fluoresce with an average depth of 1.52 cm (range, 0.90-2.60 cm) and an average diameter of 4.60 cm (range, 1.50-7.80 cm). (2) Thirteen new suspicious lesions were detected in the residual liver, with an average depth of 0.30 cm (range, 0.00-0.60 cm) and an average diameter of 0.65 cm (range, 0.20-1.20 cm). The results of intraoperative rapid frozen pathological examination showed that cirrhotic liver nodule was diagnosed in 4 patients, cancer in 3 patients (1 with high-differentiated tumor and 2 with moderate-differentiated tumor), dysplasia in 2 patients, inflammatory changes in 2 patients and fatty degeneration in 2 patients. (3) Isolated tumor specimens from 24 patients were cut along the center, with strong fluoresce on the sections. Eleven high-differentiated tumors showed tumor tissue imaging, 2 of 9 moderate-differentiated tumors showed tumor tissue imaging and 7 of 9 moderate-differentiated tumors showed annular fluorescent imaging of tumor peripheral tissue, 4 poor-differentiated tumors showed annular fluorescent imaging of tumor peripheral tissue. (4) All the 24 patients were followed up for 1 year without death, and 3 of 24 patients had tumor recurrences with an average recurrence time of 8.3 months (range, 5.0-11.0 months) and received comprehensive treatment as the main treatment of surgery. Conclution ICG mediated near infrared fluorescence imaging during the surgery can not only display the primary tumor location clearly, but also detect small lesions which are invisible by routine preoperative imaging examination or during operation, with an advantage of complete tumor clearance. Key words: Liver neoplasms; Indocyanine green; Near-infrared; Fluorography; Surgical procedures, operative