Contralateral Tumor Research Articles

Modulation of the tumor microenvironment by intratumoral administration of IMO-2125, a novel TLR9 agonist, for cancer immunotherapy.

The objective of cancer immunotherapy is to prime the host's immune system to recognize and attack malignant tumor cells. IMO‑2125, a Toll‑like receptor9(TLR9) agonist, exhibited potent antitumor effects in the murine syngeneic A20 lymphoma and the CT26 colon carcinoma models. IMO‑2125 exhibited superior A20 antitumor activity when injected intratumorally(i.t.) compared with equivalent subcutaneous doses. In mice bearing dual CT26 grafts, the i.t. injection of right flank tumors elicited infiltration of cluster of differentiation(CD)3+ T lymphocytes into tumors, resulting in the regression of injected and uninjected left flank tumors. Depletion of CD8+, but not CD4+, T‑cells abrogated the IMO‑2125‑mediated antitumor response, suggesting that CD8+ lymphocytes are required for the antitumor activity. In mice harboring right flank CT26 and left flank β‑galactosidase (β‑gal)‑expressing CT26.CL25 grafts, the i.t. administration of IMO‑2125 to the CT26 graft resulted in potent and dose‑dependent antitumor activity against the two grafts. Splenic T‑cells isolated from these mice responded to AH1 antigen (present in the two tumors) and β‑gal antigen (present only in CT26.CL25) in an interferon γenzyme‑linked immunospot assay, suggesting the clonal expansion of T‑cells directed against antigens from the two tumors. Mice with ablated CT26 tumors by previous IMO‑2125 treatment rejected re‑implanted CT26 tumor cells, but not A20 tumor cells, demonstrating that the initial IMO‑2125 treatment created a long‑lived tumor‑specific immune memory of CT26 antigens. A quantitative increase in CD3+ Tlymphocytes in injected A20 tumors and an upregulation of selected checkpoint genes, including indoleamine2,3‑dioxygenase (IDO)‑1, IDO‑2, programmed cell death protein-1(PD-1); programmed cell death protein ligand1(PD-L1), carcinoembryonic antigen‑related cell adhesion molecule1, tumor necrosis factor receptor superfamily member4(OX40), OX40 ligand, T‑cell immunoglobulin and mucin‑domain‑containing 3protein, lymphocyte‑activation gene3, cytotoxic T‑lymphocyte‑associated protein4, were observed following IMO‑2125 treatment. IMO‑2125 also increased immune checkpoint gene expression in injected and uninjected contralateral CT26 tumors, suggesting that the co‑administration of anti‑CTLA‑4, anti‑PD‑1 or anti‑PD‑L1 therapies with IMO‑2125 may provide additional therapeutic efficacy.

Heparan Sulfate Binding Coxsackievirus B3 Strain PD: A Novel Avirulent Oncolytic Agent Against Human Colorectal Carcinoma.

Coxsackievirus B3 (CVB3), a single-stranded RNA virus of the picornavirus family, has been described as a novel oncolytic virus. However, the CVB3 strain used induced hepatitis and myocarditis in vivo. It was hypothesized that oncolytic activity and safety of CVB3 depends on the virus strain and its specific receptor tropism. Different laboratory strains of CVB3 (Nancy, 31-1-93, and H3), which use the coxsackievirus and adenovirus receptor (CAR), and the strain PD, which uses N- and 6-O-sulfated heparan sulfate (HS) for entry into the cells, were investigated for their potential to lyse tumor cells and for their safety profile. The investigations were carried out in colorectal carcinoma. In vitro investigations showed variable infection efficiency and lysis of colorectal carcinoma cell lines by the CVB3 strains. The most efficient strain was PD, which was the only one that could lyse all investigated colorectal carcinoma cell lines. Lytic activity of CAR-dependent CVB3 did not correlate with CAR expression on cells, whereas there was a clear correlation between lytic activity of PD and its ability to bind to HS at the cell surface of colorectal carcinoma cells. Intratumoral injection of Nancy, 31-1-93, or PD into subcutaneous colorectal DLD1 cell tumors in BALB/c nude mice resulted in strong inhibition of tumor growth. The effect was seen in the injected tumor, as well as in a non-injected, contralateral tumor. However, all animals treated with 31-1-93 and Nancy developed systemic infection and died or were moribund and sacrificed within 8 days post virus injection. In contrast, five of the six animals treated with PD showed no signs of a systemic viral infection, and PD was not detected in any organ. The data demonstrate the potential of PD as a new oncolytic virus and HS-binding of PD as a key feature of oncolytic activity and improved safety.

Half brain irradiation in a murine model of breast cancer brain metastasis: magnetic resonance imaging and histological assessments of dose-response

BackgroundBrain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain metastases and small animal magnetic resonance imaging (MRI), we examined brain metastases’ responses from radiotherapy in the pre-clinical setting. In this study, we employed half brain irradiation to reduce inter-subject variability in metastases dose-response evaluations.MethodsHalf brain irradiation was performed on a micro-CT/RT system in a human breast cancer (MDA-MB-231-BR) brain metastasis mouse model. Radiation induced DNA double stranded breaks in tumors and normal mouse brain tissue were quantified using γ-H2AX immunohistochemistry at 30 min (acute) and 11 days (longitudinal) after half-brain treatment for doses of 8, 16 and 24 Gy. In addition, tumor responses were assessed volumetrically with in-vivo longitudinal MRI and histologically for tumor cell density and nuclear size.ResultsIn the acute setting, γ-H2AX staining in tumors saturated at higher doses while normal mouse brain tissue continued to increase linearly in the phosphorylation of H2AX. While γ-H2AX fluorescence intensities returned to the background level in the brain 11 days after treatment, the residual γ-H2AX phosphorylation in the radiated tumors remained elevated compared to un-irradiated contralateral tumors. With radiation, MRI-derived relative tumor growth was significantly reduced compared to the un-irradiated side. While there was no difference in MRI tumor volume growth between 16 and 24 Gy, there was a significant reduction in tumor cell density from histology with increasing dose. In the longitudinal study, nuclear size in the residual tumor cells increased significantly as the radiation dose was increased.ConclusionsRadiation damages to the DNAs in the normal brain parenchyma are resolved over time, but remain unrepaired in the treated tumors. Furthermore, there is a radiation dose response in nuclear size of surviving tumor cells. Increase in nuclear size together with unrepaired DNA damage indicated that the surviving tumor cells post radiation had continued to progress in the cell cycle with DNA replication, but failed cytokinesis. Half brain irradiation provides efficient evaluation of dose-response for cancer cell lines, a pre-requisite to perform experiments to understand radio-resistance in brain metastases.

Pathologic study of tumour extension for clinically localized unilateral nasopharyngeal carcinoma: Should the contralateral side be included in the clinical target volume?

The clinical target volume (CTV) delineation is crucial for tumour control and normal tissue protection. This study investigated the contralateral extension of nasopharyngeal carcinoma (NPC) in patients with a clinically diagnosed unilateral tumour to pursue the possibility of CTV reduction. Twenty NPC patients with localized tumours confined to only one side of the nasopharynx as shown by magnetic resonance imaging and fibreoptic endoscopy were selected for biopsy. The tissues of the contralateral pharyngeal recess (CPR) and the contralateral posterosuperior wall (CPSW) of the nasopharynx were obtained in each case and prepared for pathological examination. The factors associated with contralateral tumour infiltration were analysed. Five of 20 (25.0%) patients were pathologically confirmed to have carcinoma cell infiltration in the CPSW, including 2 (10.0%) that had carcinoma cell infiltration in the CPR. The T classification (P=0.014) and primary tumour volume (P=0.033) were positively associated with the infiltration of the CPSW, but none of the primary tumour factors affected the involvement of the CPR. The contralateral retropharyngeal lymph node (LN) metastasis (P=0.016), but not the contralateral cervical LN, was significantly associated with the infiltration of the CPR. Positive Epstein-Barr virus DNA (EBV-DNA) was another factor that increased the probability of CPR invasion (P=0.044). Contralateral pharyngeal recess infiltration is rare in patients with clinically diagnosed unilateral primary NPC. Reduced CTV coverage, including the CPSW but not CRP, is feasible for patients with unilateral cancer of the nasopharynx without contralateral LN metastasis or positive EBV-DNA. Further large-sample studies are needed.

Predominantly cystic clear cell renal cell carcinoma and multilocular cystic renal neoplasm of low malignant potential form a low-grade spectrum.

Multilocular cystic renal cell carcinoma has been recently excluded from clear cell renal cell carcinoma (CCRCC) category and re-designated as multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) due to its uniformly good outcomes. While strict distinction between MCRNLMP from predominantly cystic CCRCC (pc-CCRCC) is being emphasized, the significance of extensive true cystic component in CCRCC has not been investigated. Herein, we analyzed 57 MCRNLMP, 69 pc-CCRCC, and 46 non-cystic CCRCC. There were no statistically significant differences between the three subtypes in age, gender, and laterality. ISUP grades were 1 (73%) or 2 (27%) for MCRNLMP; for pc-CCRCC were 1 (31%), 2 (60%), and 3 (9%); and for non-cystic CCRCC were 1 (9%), 2 (52%), 3 (26%), and 4 (13%). MCRNLMP were either pT stage 1 (91%) or 2 (9%), pT stages for pc-CCRCC were 1 (92.5%), 2 (1.5%), and 3 (6%) and for non-cystic CCRCC were 1 (58.7%), 2 (6.5%), and 3 (34.8%). None of MCRNLMP patients developed recurrences or metastases, and only 1 contralateral kidney tumor and 1 metastasis developed in pc-CCRCC. In contrast, 19 patients with non-cystic CCRCC developed metastases (5-year PFS 58%, CI 38.3-73.5%), and 1 patient died of disease. Monosomy 3 was common in both MCRNLMP (3/3) and pc-CCRCC (6/7). This large series of MCRNLMP confirms its indolent behavior, shows that pc-CCRCC has significantly better prognosis than non-cystic CCRCC and may define the lower grade spectrum of CCRCC. We recommend that the presence and extent of CCRCC cystic component should be documented in the pathology report.

Is completion axillary lymph node dissection necessary in patients who are underrepresented in the ACOSOG Z0011 trial?

PurposeThe American College of Surgeons Oncology Group trial Z0011 demonstrated that axillary node dissection (ALND) can be omitted in patients managed with breast conserving surgery and 1 to 2 positive sentinel lymph nodes (SLNs) without adverse effects on locoregional recurrence or disease-free survival (DFS). We investigated patients with breast cancer for whom clinicopathologic features were underrepresented in the Z0011 trial and analyzed radiation therapy treatment patterns and clinical outcomes. Methods and materialsWe retrospectively reviewed records of patients who underwent a lumpectomy and SLN biopsy with positive SLNs but not an ALND and completed adjuvant radiation therapy. Eligible patients had T3 tumors, >2 positive SLNs, invasive lobular carcinoma, estrogen receptor negative status, extranodal extension, Nottingham Grade 3, or were age <50 years. ResultsWe identified 105 women treated between July 2011 and July 2016 with a median follow-up time of 48.5 months (Range, 11-83 months). There were 40 women with an extranodal extension (38.9%) and 42 women with grade 3 disease (40.0%). Nineteen patients received whole breast irradiation alone (18.1%) and 86 patients were treated with modified tangent fields including the superior axilla level I/II (81.9%). Thirty-three patients (31.4%) also received a 3rd supraclavicular, nodal-directed field. Among the 86 patients who received axillary nodal irradiation, nodal volume contouring was performed in 77 patients (89.5%). Fifty-one patients (48.6%) also received adjuvant chemotherapy. The overall rates of 4-year DFS and locoregional control (LRC) were 94.3% and 98.1%, respectively. Off all patients, 1 patient experienced an internal mammary nodal recurrence, another patient a contralateral breast tumor, and two patients distant metastases. There were no axillary or ipsilateral breast tumor recurrences. ConclusionsThis retrospective analysis of women who were underrepresented or excluded from the Z11 trial and underwent a lumpectomy and SLN biopsy with positive SLNs demonstrated comparable rates of LRC and DFS. The high rates of LRC and DFS suggest that completion ALND may be safely omitted in this patient population but larger data sets and longer follow-up times are needed to confirm this finding.

Are Multiple Tumors of the Parotid Gland Uncommon or Underestimated?

Parotid gland tumors are mostly solitary tumors of the salivary gland tissue. There is limited evidence about multifocal tumor growth of the parotid gland. We reviewed medical records of 796 consecutive parotidectomies in 758 patients over the last 40 years in our department, and investigated the incidence and histological type of synchronous and metachronous parotid tumors. Multifocal recurrent tumors and hybrid tumors were excluded. We identified 93 (13%) patients with multiple parotid lesions. Their mean age was 63 (range=15-93) years. Multiple parotid tumors were found unilaterally in 59% and bilaterally in 41% of cases. The contralateral tumor was diagnosed synchronously in 13 of 38 (34%) cases and in 25 of 38 (66%) cases metachronously. The time separating the diagnoses of both contralateral tumors ranged between one and eleven years. The same histological type was found in 95% of the tumors, and 96% of the parotid tumors had lymphatic origin. Warthin tumors (65%) were the most frequent histological type. Every sixth patient with a parotid tumor has multifocal tumor lesions. The majority of multifocal parotid tumors have a lymphoid element, while multifocal growth is uncommon in other histological types.

Nephrectomy, inferior vena cava thrombectomy in renal cell carcinoma with tumor venous thrombosis and pulmonary metastases

Objective: to assess advisability of nephrectomy, inferior vena cava (IVC) thrombectomy in renal cell carcinoma (RCC) with tumor venous thrombosis and pulmonary metastases. Materials and methods. We analyzed medical data of 112 consecutive RCC patients with tumor venous thrombosis and pulmonary metastases undergone nephrectomy, IVC thrombectomy at N.N. Blokhin Cancer Center from 1971 to 2014. Median age was 57 (19–77) years, a male-to-female ratio – 4.1:1. Tumor venous thrombosis occurred in all patients and achieved levels III–IV in 36 (32.1 %) cases. Ten (8.9 %) patients had solitary, 102 (91.1 %) – multiple lung metastases. Nephrectomy, thrombectomy was performed in all cases, 10 (8.9 %) patients also underwent complete resection of all pulmonary lesions. Eighty-eight (78.6 %) patients managed to receive systemic therapy. Median follow-up – 24 (3–148) months. Results. Median operative time was 185 (70–380) min, median blood loss – 4000 (200–18 000) ml. Intraoperative complications occurred in 25 (22.3 %), postoperative – in 37 (33.0 %) patients (Clavien–Dindo grade III–V – 27 (24.1 %)). Mortality rate was 9.8 %. Five-years overall and cancer-specific survival in all patients were 22.3 and 24.0 % respectively (median – 21.0 ± 3.6 and 21.0 ± 2.9 months respectively). Independent negative prognostic factors for cancer-specific survival were tumor pulmonary embolism before surgery (hazard ratio 269.4; 95 % confidence interval 112.4–314.6; р = 0.021) and contralateral renal vein tumor thrombosis (hazard ratio 83.1; 95 % confidence interval 78.2–178.3; р = 0.011). Conclusion. Nephrectomy, IVC thrombectomy is justified in selected RCC patients with tumor venous thrombosis and lung metastases without pulmonary embolism before surgery and contralateral renal vein tumor thrombosis. Nephrectomy, IVC thrombectomy is associated with acceptable complications rate and provides long-term survival comparable with the results of simple cytoreductive nephrectomies in historical series.

Comparison and evaluation of two RGD peptides labelled with 68Ga or 18F for PET imaging of angiogenesis in animal models of human glioblastoma or lung carcinoma.

The aim of this study was to evaluate two RGD radiotracers radiolabelled with fluorine-18 or gallium-68, in detecting angiogenesis in grafted human tumours and monitoring their treatment with the anti-angiogenic agent bevacizumab.Sixteen mice bearing an U87MG tumour in one flank and a contralateral A549 tumour were treated with intravenous injections of bevacizumab twice a week for 3 weeks. PET images with 18F-RGD-K5 and 68Ga-RGD were acquired before treatment (baseline), after three bevacizumab injections (t1) and after seven bevacizumab injections (t2).In A549 tumours, the treatment stopped the tumour growth, with a tumour volume measured by calliper remaining between 0.28 and 0.40 cm3. The decrease in tumour uptake of both RGD tracers was non-significant. Therefore it was not possible to predict this efficacy on tumour growth based on RGD PET results, whereas ex vivo measurements showed a significantly lower tumour uptake of both tracers in mice sacrificed at t2 vs. at baseline.In U87MG tumours, the uptake measured on PET decreased during treatment, reflecting the partial therapeutic effect observed on tumour volume, consisting in a decrease in the slope of tumour growth. Using 18F-RGD-K5, this decrease in tumour SUVmax became significant at t1, whereas it was also observed with the 68Ga-RGD tracer, but only at t2. 18F-RGD-K5 appeared more efficient than 68Ga-RGD in the visualisation and follow-up of U87MG tumours.The comparison of those results with those of immunohistochemistry at baseline and at t2 favoured the hypothesis that tumour RGD uptake reflects other cancer properties than just its angiogenic capacity.

Microsurgery for patients diagnosed with neurofibromatosis type 2 complicated by vestibular schwannomas: Clinical experience and strategy for treatments.

Most patients diagnosed with neurofibromatosis type 2 (NF2) have bilateral vestibular schwannomas (VS). Through reviewing surgical method and clinical outcomes, we tried to find out a strategy for treatments in NF2 patients with VS.We retrospectively reviewed patients diagnosed pathological NF2 and have had microsurgery (MS) for VS in the PLA Army General Hospital. Seventeen patients were included from January 2000 to December 2016. Fifteen patients had progressive hearing impairment, and 7 ears were totally deaf. Computed tomography and magnetic resonance imaging were used for preoperative and postoperative evaluation. House–Brackmann (H-B) classification was used to evaluate facial function, and the hearing outcome was classified according to American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) hearing classification system. The outcomes included functional hearing, facial function, and complications.In the 17 patients, 9 were men, and the mean age was 27.2 years old. The mean duration of disease was 38.4 months. Twenty-six VS were excised. Nine patients with bilateral VS and unilateral surgery had repeated surgery for the contralateral tumor after 3 to 12 months. The hearing preservation rate was 41.6%. In the 26 excisions for VS, 24 had intact facial nerve. In the other 2 tumor excision, damaged facial nerves had head-to-head adhesion using biological fibrin glue. The rate of facial nerve function preservation was 60%. No mortality or major complication was reported. The follow-up time ranged from 11 to 78 months with a mean value of 39 months.MS is an effective treatment for NF2 patients with VS. The operation for bilateral VS should be staged according to tumor size and bilateral hearing function. However, methods on how to preserve functional hearing and facial function remain the issue. Further randomized controlled studies are needed to find out a better treatment for NF2 patients with VS according to the overall condition.

Nephron-sparing Surgery for Syndromic Wilms' Tumor: Robotic Approach

The current standard treatment for stage I Wilms' tumor is open radical nephrectomy. Patients with WAGR syndrome and Wilms' tumor have risk of contralateral tumor and are a group of patients benefitted by nephron-sparing surgery (NSS). Whereas laparoscopic NSS has been attempted in such patients, due to the inherent technical limitations it has failed to gain popularity. Robotic approach for NSS overcomes limitations of movement and dexterity occurring with laparoscopic approach. However, the existing literature in robotic NSS in children is very limited. We present the first report of robotic approach for NSS in a child with WAGR syndrome.

Validation of the current eligibility criteria for focal therapy in men with localized prostate cancer and the role of MRI.

To validate current eligibility criteria for focal therapy (FT) in prostate cancer men undergoing radical prostatectomy (RP) and to assess the role of magnetic resonance imaging (MRI). Retrospective analysis of 217 RP patients (2009-2016) with preoperative MRI (almost all in external institutions) and fulfillment ofdifferent FT eligibility criteria: unilateral tumor, clinical tumor stage ≤cT2a, prostate volume ≤60mL and either biopsy Gleason 3+3 or ≤3+4 and PSA ≤10 or≤15ng/mL. Multivariable logistic regression analyses (MVA) assessed the role of MRI to predict the presence of significant contralateral tumor or extracapsular extension (ECE), including seminal vesicle invasion. To quantify model accuracy, Receiver Operating Characteristics-derived area under the curve (AUC) was used. Of 217 patients fulfilling widest biopsy criteria and 113 fulfilling additional MRI criteria, 64 (29.7%) and 37 (32.7%) remained eligible for FT according to histopathological results. In MVA, fulfillment of MRI criteria reached independent predictor status for prediction of contralateral tumor but not for ECE. Addition of MRI resulted in AUC gain (57.5-64.6%). Sensitivity, specificity, PPV and NPV for MRI to predict contralateral tumor were: 41.8, 71.6, 70.9 and 42.6%, respectively. Virtually the same results were recorded for Gleason 3+3 and/or PSA≤10ng/mL. Patient eligibility criteria for FT using biopsy criteria remained insufficient with respect to contralateral tumor disease. Although, MRI improves accuracy, it cannot safely exclude or minimize chance of significant cancer on contralateral prostate side. To date, stricter eligibility criteria are needed to provide more diagnostic reliability.

Abstract P4-05-01: G protein-coupled estrogen receptor expression in lymph node metastasis and contralateral breast cancer during endocrine treatment

Abstract Background: G protein-coupled estrogen receptor (GPER) is a putative estrogen receptor (ER) with potential clinical implications in breast cancer. Depending on subcellular location, cut-off and treatment, GPER has been proposed as both a marker of aggressive disease and of good prognosis. The correlation with known prognostic factors appears to be biphasic. Furthermore, plasma membrane GPER-overexpression (GPERPM) is associated to a worse prognosis, suggesting potential receptor mutation or amplification. In vitro studies also show that tamoxifen upregulates GPER in breast cancer cells, suggesting GPER as a mediator of endocrine resistance. To further clarify the role of GPER in breast cancer and endocrine treatment we studied GPER during evolution from primary tumor to lymph node metastasis (lgl-met), and from first tumor (BC1) to a second contralateral tumor (CBC), with/without endocrine treatment (mainly tamoxifen) in between. As a CBC developed despite adjuvant treatment given for BC1 is presumably resistant to this treatment, it may be used to study endocrine treatment escape mechanisms in vivo. Patients and methods: From a well-defined population-based cohort of CBC-patients we constructed a unique tissue-microarray including 688 patients with metachronous CBC. Overall GPER staining intensity (0-5) (GPERoverall) and GPERPM (present/absent) was evaluated by two investigators in BC1 (n=559), CBC (n=595) and corresponding lgl-met (nBC1=151 and nCBC=158). Impact on survival was analyzed using the Kaplan-Meier method and Cox regression, and p-values calculated with the log rank test. Association was tested with a chi-square test (for trend when appropriate), and differences between paired samples with Wilcoxon signed rank test. Results: GPR30overall showed the expected biphasic association with ER-α and the progesterone receptor (PgR) in BC1 and CBC, where high and low GPER expression associated with ER/PgR negativity (p&amp;lt;0.001). High GPER expression was also associated with increased Ki67 expression (p=0.04 and p=0.08). Similar results were seen for GPERPM (ER/PgR-negativity p&amp;lt;0.001, high Ki67 p&amp;lt;0.001). There was no association between GPER in BC1 and CBC, and prior endocrine treatment did not seem to affect GPER expression in CBC. However, a significant association between primary tumor and corresponding lgl-met was seen in both BC1 and CBC. Further, a comparison between BC1/CBC and corresponding lgl-met showed a decrease in GPERoverall (p&amp;lt;0.001), but an increase in GPERPM (p=0.01). A high CBC GPER expression was associated with a worse OS, both when considering GPERoverall (p=0.02, HR=1.18, 95%CI: 1.05-1.32) and GPERPM (p=0.007, HR=1.61 95%CI: 1.14-2.29). Similar results were seen when analyzing survival in relation to CBC lgl-met GPER expression. Conclusion: A high GPER expression in CBC and matched lgl-met is associated with worse OS. The overall expression of GPER decreases from primary tumor to lgl-met, but plasma membrane staining increases, supporting a mutation or amplification of the receptor. In addition, GPER expression correlates with other markers of aggressive disease, highlighting the potential as a novel treatment target. However, prior tamoxifen treatment did not alter tumor GPER expression. Citation Format: Sjöström M, Fernö M, Rydén L, Leeb-Lundberg FLM, Alkner S. G protein-coupled estrogen receptor expression in lymph node metastasis and contralateral breast cancer during endocrine treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-05-01.

Third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice.

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third‐generation oncolytic herpes simplex virus type 1 (HSV‐1) T‐01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T‐01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T‐01 were tested in 14 human and 1 murine hepatoma cell line in vitro. In various mouse xenograft models, HuH‐7, KYN‐2, PLC/PRF/5 and HepG2 human cells and Hepa1‐6 murine cells were used to investigate the in vivo efficacy of T‐01. T‐01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T‐01 compared with that of mock‐inoculated tumors. In a bilateral Hepa1‐6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T‐01 was inhibited, as was the case for contralateral tumors. T‐01 also significantly reduced tumor growth. T‐01 infection significantly enhanced antitumor efficacy via T cell‐mediated immune responses. Results demonstrate that a third‐generation oncolytic HSV‐1 may serve as a novel treatment for patients with HCC.

Characteristics of testicular tumors in prepubertal children (age 5–12 years)

Testicular tumors in children have two peaks with different types of tumors; in the first 4 years of life a third to half are benign with increased risk of malignancy during puberty. The pathology of testicular tumors between these peaks, at the age of 5-12 years, is not known. We hypothesized that because of the low level of testosterone at this time, the incidence of malignant tumors is very low. To compare malignancy risk of primary testicular tumors in children in the prepubertal period (5-12 years) compared with younger (0-4 years) and pubertal (13-18 years) children. We retrospectively (2002-2016) identified patients <18 years with surgery for primary testicular tumor. Patients with testicular tumor risk were excluded. Ultrasound studies were reviewed for contralateral testis volume, tumor morphology, and tumor maximal diameter, for three age groups: 0-4, 5-12, and 13-18 years. The Freeman-Halton extension of the Fisher exact probability test was adopted for categorical outcomes, and one-way ANOVA for continuous outcomes. Fifty-two patients (mean age 11.0 years, range 6 days-18 years) were identified. Malignant tumor prevalence significantly differed (p<0.01) among age groups (Fig).: 0-4 (72.7%, 8/11), 5-12 (0%, 0/16), and 13-18 years (44.0%, 11/25). The most common tumor types in 5-12 years were epidermoid cyst (31.3%, 5/16) and tumor mimics (37.5%, 6/16). Prevalence of cystic tumors in 5-12 year olds was not significantly different compared with other age groups. Contralateral testicular volume >4mL (pubertal surge) significantly (p<0.01) differed among groups: 0-4 years (0/11), 5-12 years (3/16), and 13-18 years (19/20). In children aged 13-18 years the mean tumor maximal diameter (29.8±4.4mm) was significantly larger (p<0.01) compared with children 5-12 years (9.3±5.5mm) and all malignant tumors had contralateral testicular volume >4mL. We found that preadolescent children between the ages of 5 and 12 years have distinctive characteristics compared with the other age groups. Most importantly, no malignant testicular tumors were found in this age group. About a third of the children presented with an incidental testicular mass. The testicular tumors were significantly smaller (9.3±6.7mm) compared with those in children aged 13-18 years (29.8±4.4mm). There were limitations because of the retrospective nature of the study. We found no malignant testicular tumors in children aged 5-12 years with no risk factors and prior to pubertal surge. Our study suggests use of more conservative treatment in this group of patients.

Reversing immune checkpoint inhibitor resistance with adenoviral IL-24 and p53 tumor suppressor immune gene therapy.

64 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients either do not respond or become resistant to this therapy. Methods: We evaluated the ability of tumor suppressors p53 and IL-24, delivered via adenoviral vectors, to reverse immune checkpoint inhibitor resistance and induce abscopal therapeutic effects in the highly immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of immune checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before intra-tumoral delivery of adenoviral vectors encoding tumor suppressors p53 (Ad-p53) or IL-24 (Ad-IL24). Results: Anti-PD-1 had minimal or no therapeutic efficacy when compared to PBS controls. However, there was a reversal of anti-PD-1 resistance in animals treated with Ad-p53, or Ad-IL24, in combination with anti-PD-1. Evaluation of primary tumor growth using ANOVA confirmed synergistic effects of the combination treatments over either agent used as monotherapy (p = 0.0001 for p53, p = 0.002 for IL-24). We also observed statistically significant decreases in contralateral abscopal tumor growth in animals whose primary tumors were treated with either Ad- p53 or Ad-IL24 (p = 0.046, and p = 0.0021, respectively) or in combination with anti-PD-1 (p = 0.02 p53, and p &lt; 0.0001 for IL-24) as compared to animals treated with anti-PD-1 alone. With respect to survival, combined tumor suppressor + anti-PD-1 therapy resulted in a statistically significant increase in survival compared to: a) tumor suppressor therapy alone (p = 0.01 for either Ad-p53 and or IL-24) and b) anti-PD-1 therapy alone (p &lt; 0.001 for p53, and p = x for IL-24). Conclusions: Overall, these results indicate that IL-24 and p53 tumor suppressor immune gene therapy can reverse immune checkpoint inhibitor resistance in primary tumors, and induce abscopal effects inferring the activation of systemic anti-tumor immune responses that reverse resistance to immune checkpoint inhibitor therapy.

Palliative surgery for Krukenberg tumors - 12-year experience and review of the literature.

AIMTo determine the clinical characteristics of patients undergoing palliative surgery for Krukenberg tumors, including disease presentation, outcomes, and prognostic factors.METHODSThis was a retrospective clinical study of all patients who underwent palliative surgery for Krukenberg tumors between January 2004 and December 2015. Patient information was obtained from inpatient and outpatient case notes as well as the hospital electronic records. Patients who underwent potentially curative resection, and patients with Krukenberg tumors who did not undergo surgery were also excluded from the study. Palliative surgery was defined as those performed for either alleviation of symptoms or for asymptomatic patients for whom surgical removal of the tumors were deemed necessary following a multidisciplinary consensus. Tumors were diagnosed pre-operatively by computed tomography scans and all had histologic confirmation of the surgical specimens.RESULTSOver the study duration, 38 female patients underwent palliative surgery for Krukenberg tumors at our institution. Mean age was 54.2 ± 11.7 years. The colon was the most frequent primary source of metastases (n = 21) followed by the stomach (n = 4). Prophylactic palliative surgery was performed for eight (21.1%) asymptomatic patients. Median post-operative length of stay was 8 d (IQR 6-12 d). Five patients (13.2%) experienced post-operative complications, although high grade morbidity was only seen in one patient (2.6%). Median overall survival from surgery was 17 mo (95%CI: 12.1-21.9) at a median follow-up duration of 12 mo (IQR 8-17 mo). The median survival was shorter for patients who underwent emergency surgery, younger patients, those with a colorectal primary, larger tumors, or synchronous peritoneal or hepatic metastases.CONCLUSIONPalliative surgery for Krukenberg tumors can be performed safely with acceptable complication rates. Bilateral oophorectomy should be performed to prevent the risk of symptomatic contralateral tumors.

Effect of a third-generation oncolytic herpes simplex virus on the growth of human hepatocellular carcinoma.

321 Background: Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 replicates efficiently and selectively in tumor cells, kills tumor cells without damaging the surrounding normal tissues, and induces host immune responses specific to tumor cells. Here we investigated the antitumor effects of T-01 on HCC. Methods: The cytopathic activities of T-01 were tested at different multiplicities of infection in 14 human and one murine hepatoma cell lines in vitro. In mouse various xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. Results: T-01 was cytotoxic to 13 cell lines (in vitro), including 10 human HCCs, two human hepatoblastomas, and one murine hepatoma. In mouse xenograft models of subcutaneous, orthotopic, and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the HCC cell lines HuH-7, KYN-2, and PLC/PRF/5 as well as those formed by the hepatoblastoma cell line HepG2 was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited and, in the contralateral tumors without T-01, T-01 also significantly reduced tumor growth compared with mock-infected tumors. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Conclusions: These results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.

Robot-Assisted Partial Nephrectomy for Multiple Renal Tumors: A Vattikuti Collective Quality Initiative Database Analysis

Abstract Introduction: Patients with multiple renal tumors may have a higher chance of metachronous contralateral renal tumors.1 Owing to this, efforts must be made to utilize nephron sparing surgery in these cases, wherever possible. Longer ischemia times are expected because of resection and reconstruction of multiple defects. The outcomes of robot-assisted partial nephrectomy (RAPN) for this indication have previously been reported to be comparable with solitary tumors.2,3 However, other series have shown an increased complication rate.4 The three goals of surgery are to remove all the tumor with acceptable ischemia time and low complication rate. This video shows the technique and outcomes of RAPN for multiple tumors in a single operative session in a multi-institutional setting. Materials and Methods: Retrospective analysis of the Vattikuti Collective Quality Initiative prospective database was done. A total of 501 patients underwent RAPN from November 2014 till January 2017 at 14 institutions in 9 c...

Microsurgical Endoscope-Assisted Gravity-Aided Transfalcine Approach for Contralateral Metastatic Deep Medial Cortical Tumors.

Microsurgical Endoscope-Assisted Gravity-Aided Transfalcine Approach for Contralateral Metastatic Deep Medial Cortical Tumors.