Body Tumor Research Articles

Examination of necrosis in tumors treated with AVM0703 compared to chemotherapy.

e20029 Background: AVM0703 should be the first choice for no-option cancer patients. AVM0703 is a fast-acting formulation that lympho-ablates while sparing HSCs, MSCs, platelets, and RBCs. Its transient and manageable side effects reduce the need for additional maintenance treatments while improving quality of life. AVM0703 induces a novel NKT that induces tumor-killing activity without causing GvHD or CRS. AVM0703 is a versatile formulation that can be safely redosed or given in combination with known chemotherapeutics. It is predicted to be safe for previously neglected patient populations. Methods: Mice were monitored over the course of 13 weeks or endpoint criteria. Body weights and tumor measurements were taken 3x per week. Both group and individual growth was tracked. Tumors were dissected from the right flank on takedown and fixed for 24 hours in 4% paraformaldehyde, then stored in 70% ethanol. For analysis, tumors were sent to HistoTox Labs, embedded in paraffin blocks, then sliced and stained for H&E. In a separate study, mice with subcutaneous A20 were treated with increasing concentrations of AVM0703 and allowed to go to endpoint. Tumors were dissected and stained for H&E, CD3, NKp46, and AC3. Finally, tumor bearing mice were treated with high doses of AVM0703 48 hours before takedown. Tumors were dissected and sent to HistoTox for embedding, slicing and staining for H&E, NKp46, CD3, CD49b, AC3, CD31, B220, Ly6G, Sca-1, and PSR. Results: Mice treated with repeat doses of AVM0703 did not display significant loss of body weight or worsening of condition, which was observed in mice treated with chemotherapy. All combination mice displayed significantly higher tumor necrosis and resorption compared to all other treatment groups. Significant necrosis was observed in tumors in as little as 48 hours post dosing. At endpoint, apoptosis was slightly increased at all doses compared to placebo. CD3 and CD49b were decreased in doses above 18 mg/kg, indicating activation of NKT cells in comparison to placebo and low dose AVM0703. There was also an increase in NKp46 staining along the border of large necrotic regions within the tumor. While necrosis was prevalent within the tumor, there was only a slight increase in apoptosis staining. Conclusions: AVM0703 can be repeatedly dosed without significant signs of toxicity. A single dose after 48 hours displays large regions of necrosis within the tumor, indicating that AVM0703 is a fast-acting formulation. AVM0703 is able to replace a dose of Cy/Flu in mice with similar efficacy and increased tumor killing in comparison to Cy/Flu alone with less toxicity.

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort.

6084 Background: Uterine serous carcinoma (USC) is a rare and aggressive malignancy, accounting for 40% of all endometrial cancer deaths. Human Epidermal Growth Factor Receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in USC. Given recent randomized trial results, HER2-directed therapy is now recommended in advanced-stage or recurrent, HER2-positive disease. The significance of tumoral HER2 expression in early-stage disease has not yet been established. Methods: In this IRB-approved, retrospective, multi-institutional cohort, women diagnosed with stage I USC from 2000-2018 were identified. Patient demographic, treatment, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0-3+. Equivocal IHC results (2+) were further tested with in-situ hybridization (ISH) per the 2007 ASCO-CAP HER2 breast cancer guidelines. HER2 overexpression (“positive”) was defined as 3+ IHC or ISH positive. Kaplan-Meier analyses and Cox-proportional hazards were used to compare survival between the cohorts. Results: In total, 173 patients with stage I USC were tested for HER2; 25% were HER2-positive, 77.4% had stage IA and 22.6% had stage IB disease. Adequate clinical follow up was available for 168 patients. There were no significant differences in age, race/ethnicity, body mass index, surgical management, sub-stage, tumor size, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. On univarite analysis, presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p=0.003). After a median follow-up of 50 months, there were 41 (24.4%) recurrences. Significantly more recurrences were observed in the HER2-positive cohort (47.6% vs. 16.7%, p<0.001). HER2 overexpression was also associated with poorer progression-free (PFS) and overall survival (OS) (p<0.001 and p=0.012). After adjusting for prognostic factors including sub-stage and adjuvant treatment, those with HER2-positive tumors experienced inferior PFS (aHR 3.67, 95%CI 1.92-6.98; p<0.001) and OS (aHR 2.03, 95%CI 1.03-4.01; p=0.042) compared to HER2-negative tumors. Conclusions: Uterine serous carcinoma is a poor prognostic tumor, even in patients with early-stage disease. Given its significant association with worse survival outcomes, tumoral HER2 overexpression appears to be a prognostic biomarker in women with stage I disease. These data provide rationale for clinical trials with HER2-directed therapy in early-stage uterine serous carcinoma.

Clinical study on the tunnel approach in laparoscopic radical right hemicolectomy.

e16135 Background: The medial to lateral approach Laparoscopic right hemicolectomy complies with the “no-touch” principle, but need a demanding procedure with a steep learning curve. This study was designed to assess the superiority of the tunnel approach compared to traditional medial-to-lateral approach in laparoscopic right hemicolectomy for patients with right-sided colon cancer. Methods: The new method was called Tunnel Approach: The tunnel was formed with Toldt's gap was dissociated upward from the attachment of ileocecal part and retroperitoneum, then the right mesocolon was lifted to expose and divide the superior mesenteric blood vessel. We analyzed retrospectively the patients with resectable right-sided colon cancer confirmed by colonoscope and imaging who received the laparoscopic radical right hemicolectomy. The patients were divided into the tunnel approach (group A) and the traditional medial-to-lateral approach (group B) according to the surgical maneuver performed. Results: A total of 84 patients who received laparoscopic radical right hemicolectomy were assigned to group A (n = 42) or group B (n = 42) between January 2016 to June 2017. There was no difference in baseline characteristics including demographics, body mass index (BMI), tumor stage, tumor location and differentiation. The operation time and intraoperative blood loss in group A were significantly better than group B (137.74±22.7 vs. 153.1±28.8min, p < 0.05; 49.0±40.7 vs. 142.9±87.4ml, p < 0.05, respectively).There was no difference in tumor size(5.7±2.1 vs. 5.7±2.1cm, p>0.05), conversion to laparotomy rate(0 vs. 3, p>0.05), lymph node yield(30.5±14.4 vs. 27.9±12.7, p>0.05), time to first flatus(3.4±1.3 vs. 4.0±1.3d, p>0.05), postoperative hospital stays(10.0±2.2 vs. 12.3±3.0d, p>0.05) and complications(2 vs. 3, p>0.05) between two groups. There was no treatment-related death in both groups. Conclusions: The characteristic of “tunnel” approach is to convert the anatomy from a two-dimensional to a three-dimensional view, it showed the benefits of both speed and safety with low intraoperative conversion to laparotomy rate and mortality. This new tunnel approach right hemicolectomy is worth recommended.

Clinicopathologic and protein markers distinguishing POLE and copy-number low group in endometrial cancer.

e18110 Background: Requirement of DNA sequencing to diagnose POLE group is a barrier for adoption of molecular subtyping in endometrial cancer. We aimed to identify clinicopathologic and protein markers distinguishing POLE and copy-number (CN) low group in endometrial cancer. Methods: Ninety-one samples (POLE: 15, CN low 76) classified as POLE or CN low groups by integrative clustering were selected from The Cancer Genome Atlas endometrial cancer dataset. Clinicopathologic variables and normalized reverse phase protein array expression data were extracted. We first selected clinicopathologic variables associated with group (POLE vs CN low) via univariate analysis. Then, we identified protein makers using the logistic regression model with significant clinicopathologic variables as adjusting covariates. The differentially expressed proteins were selected based on q-value of the false discovery rate for multiple comparison. With various q-value cut-off ( < 5%, 10%, 20%), several logistic models including differentially expressed markers were constructed by stepwise selection method using the area under curve (AUC) from 5-fold cross-validation (CV). Results: Among clinicopathologic variables, body mass index (BMI) and tumor grade were associated with group (p = 0.02 and p < 0.01, respectively). Being adjusted for BMI and tumor grade, 5 proteins were associated with group in q-value cut-off of < 5%. The model including clinicopathologic variables and 5 proteins identified BMI, Cyclin B1, Caspase 8, and XBP1 as markers distinguishing POLE and CN low groups. The mean of CV AUC, sensitivity and specificity of the selected model were 0.97, 0.97, and 0.60, respectively. Conclusions: BMI and expression levels of Cyclin B1, Caspase 8, XBP1 are candidate markers distinguishing POLE and CN low group. A further validation study using immunohistochemical staining is necessary to facilitate the adoption of molecular subtyping as daily practice.

Clinicogenomic predictors of extreme responses to anti-PD1/PDL1 checkpoint inhibitors (CPI) in metastatic urothelial cancer (mUC).

5050 Background: Only a subset of mUC patients (pts) derives benefit from CPI. We sought to evaluate potential clinical and genomic predictors, with additional focus on extreme outcomes. Methods: CPI-treated mUC with tumor sequencing with MSK-IMPACT (up to 468 genes) were identified. Pre-CPI clinical variables (including hemoglobin [hgb], lymphocyte [lymph], neutrophil [neut] and eosinophil [eos] counts) were extracted. Endpoint was time on treatment (ToT). Poor responders were defined as ToT ≤9 weeks and overall survival ≤3 months; exceptional responders had ToT >20 months. A multivariate Cox model for ToT was performed with clinical variables chosen by stepwise selection minimizing Akaike information criterion. Genomic analyses were adjusted for multiple testing. Results: 166/171 identified mUC were evaluable. Median age was 68 years, 78% were male. 72% had bladder primary, while 17%, 35% and 28% had liver, lung and bone metastases (mets). 67% had prior platinum chemo. 24 pts (14%) were poor and exceptional responders, respectively. In univariate analysis, liver mets were associated with shorter ToT while DNA damage repair (DDR) gene alterations, higher body mass index (BMI), eos, hgb and tumor mutation burden (TMB) were associated with longer ToT. No specific genomic alterations achieved q<.05. In multivariate model, prior chemo (HR 1.6, p=.01), liver mets (HR 2.4, p<.01) and high neut were associated with shorter ToT while urethral primary (HR 0.1, p<.01), higher TMB (HR 0.9, p<.01) and higher eos (HR 0.1, p<.01) were independently associated with ToT. Univariate logistic regression to identify poor and exceptional responders are tabulated. Multivariate results will be reported. Conclusions: In addition to validation of various known mUC prognosticators, we observed potential non-linear influence of clinical and genomic factors on extreme outcomes. [Table: see text]

Association of Oxidative Stress and Production of Inflammatory Mediators Matrix Metalloproteinase-9 and Interleukin 6: Systemic Events in Radicular Cysts.

BackgroundMatrix metalloproteinase-9 (MMP-9) and antioxidants are associated with the pathogenesis of cysts and may initiate and sustain the formation of new capillaries.ObjectiveThe objective of this study was to determine the association of oxidative stress and the production of inflammatory mediators MMP-9 and interleukin 6 (IL-6) in systemic events in radicular cyst growth.Materials and methodsFifty patients (34 men, 16 women) with periapical granulomas and radicular cysts were included in this cross-sectional study. Twenty subjects (12 men, eight women) with no signs of periodontal diseases were recruited as controls. Blood serum levels of MMP-9, IL-6, superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GPx) were recorded. We also recorded body mass index (BMI) and tumor necrosis factor-alpha (TNF-alpha) levels.ResultsThe mean age of the test group patients and control patients was 45.9 and 48.8 years, respectively. The BMI of test group patients (23.77± 3.88 kg/m2) was higher than that of the controls (27.98 ± 3.88 kg/m2; p ≤ 0.000). Levels of serum MDA (p ≤ 0.033), IL-6 (p ≤ 0.041), TNF-alpha (p ≤ 0.004), and MMP-9 (p ≤ 0.033) were significantly increased in patients as compared with control values. SOD (p ≤ 0.003) and GPx (p ≤ 0.033) levels were significantly reduced in patients as compared with controls.ConclusionOxidative imbalance and the increased production of inflammatory mediators may be associated with systemic events in radicular cysts. Bone-resorbing mediators and proinflammatory cytokines that were evaluated in the study (MMP-9, IL-6, C-reactive protein, TNF-alpha) were also elevated in the serum of the ailing group, thus documenting a well-established role for these circulating biochemical variables in the course of the progression and pathogenesis of radicular cyst development.

A Novel Technique for Pancreatic Stump Closure: Clip Ligation of the Duct and Associated Suturing of Pancreas.

Pancreatic fistula (PF) remains the primary source of morbidity after distal pancreatectomy (DP). There is currently no optimal stump closure technique to reduce PF rates. We present a novel technique for pancreatic stump closure using Clip Ligation of the duct and Associated Suturing of Pancreas (CLASP). Five patients (three females) with a median age of 65 years underwent DP and splenectomy for pancreatic body or tail tumour using the CLASP technique. Four of those operations were done laparoscopically. Only one patient developed grade A PF. No other postoperative complications were noticed. The mean length of stay was 5.4 days. The CLASP technique was applicable in both laparoscopic and open distal pancreatectomy. The key points include mobilisation of the pancreatic body from the retroperitoneum and division of the parenchyma with energy device. The technique of pancreatic stump closure involves the isolation of the pancreatic duct (PD), application of a double ligaclip on the proximal duct, division of the PD and finally suturing of the pancreatic stump. The CLASP technique is an effective and safe alternative technique to the current traditional methods of pancreatic stump closure.

载芬维A铵脂质体抑制A375黑素瘤细胞裸鼠皮下移植瘤的初步研究

Objective To evaluate the inhibitory effect of fenretinide-loaded liposomes (4-HPR-L) on subcutaneous transplanted malignant melanomas in nude mice. Methods A film-ultrasonic dispersion method was used to prepare 4-HPR-L. BALB/c nude mice were subcutaneously inoculated with A375 melanoma cells in the right axillary fossae to establish malignant melanoma-bearing nude mouse models. Ten nude mouse models were randomly and equally divided into 2 groups to be injected with near-infrared fluorescent cell membrane label (DiR) solution or DiR liposomes (DiR-L) at the same concentration in the caudal vein, and a live imaging system was used to observe the distribution of DiR or DiR-L in nude mice at 6, 12, 24 hours after the injection. Another 30 nude mice were randomly and equally divided into 3 groups to be injected with 5% (mass fraction) glucose solution at a single-dose of 0.2 ml (control group) , 25 mg/kg 4-HPR solution (4-HPR group) and 25 mg/kg 4-HPR-L solution (4-HPR-L group) respectively on days 8, 10, 12, 14, 16, 18, 20 and 22 after the inoculation with A375 cells. The mouse body weight and tumor volume were dynamically monitored in the above groups after the injection, and the survival situation was observed. The nude mice were sacrificed on day 2 after the final injection, and the heart, liver, spleen, lung, kidney and tumor tissues were resected. These tissues were subjected to hematoxylin-eosin staining and immunohistochemical staining to observe the metastasis of melanoma in mice, and terminal deoxyribonucleotidyl transferase-mediated nick end labelling was performed to detect the apoptosis in tumor cells. One-way analysis of variance and independent-sample t test were used to analyze measurement data. Results The live imaging system showed that DiR-L could be retained in melanoma for a long time, and strong fluorescence of DiR-L could be still observed in the tumors at 24 hours after injections. Quantitative fluorescence analysis revealed that the fluorescence intensity of DiR-L (22.85 ± 1.66) was significantly higher than that of DiR in tumor tissues (8.45 ± 0.97, t = 12.957, P < 0.01) . Compared with the control group and 4-HPR group, the resected tumor weight on day 2 after the final injection was significantly decreased in the 4-HPR-L group (F = 27.055, t = 4.768, 6.640, respectively, both P < 0.05) . Hematoxylin-eosin staining showed that liver metastasis occurred in 2 nude mice in the 4-HPR-L group, but in all the nude mice in the control group and 4-HPR group. All the nude mice in the 4-HPR-L group died within 76 days after inoculation, and the mice in the control group and 4-HPR group all died within 56 and 59 days respectively after inoculation. There were significant differences in the apoptotic index among the control group (12.14‰ ± 1.33‰) , 4-HPR group (67.17‰ ± 15.18‰) and 4-HPR-L group (152.73‰ ± 11.27‰; F = 167.588, P < 0.05) , and the apoptotic index was significantly higher in the 4-HPR-L group than in the control group and 4-HPR group (t = 18.162, 11.075 respectively, both P < 0.05) . Conclusion 4-HPR-L can effectively inhibit the growth of subcutaneous melanoma in nude mice and metastasis of melanoma cells, and prolong the survival duration of nude mice. Key words: Nevi and melanomas; Fenretinide; Liposomes; Models, animal; Apoptosis; A375 cells

Case report: optimal tumor cytoreduction and octreotide with durable disease control in a patient with MEN-1 and Zollinger-Ellison syndrome\u2014over a decade of follow-up

BackgroundZollinger-Ellison syndrome (ZES) is a rare condition characterized by hypersecretion of gastrin by gastrinoma tumors leading to severe peptic ulcer disease with potential development of gastric carcinoid tumors. Herein, we report the clinical course of a 68-year-old patient with multiple endocrine neoplasia type 1 (MEN-1) who underwent several surgeries to ultimately undergo optimal tumor cytoreduction of locally advanced gastrinomas and symptomatic gastric carcinoids. The patient was subsequently maintained on octreotide long-acting release (LAR). This case report supports consideration for aggressive tumor cytoreduction and octreotide in similar patients with MEN-1-associated ZES for durable disease control and symptom management.Case presentationThe patient is a 68-year-old male with multiple endocrine neoplasia type 1 (MEN-1), diagnosed in 1993 after presenting with recurrent renal calculi and hypercalcemia. Soon thereafter, he presented with symptoms and elevated gastrin levels suggestive of ZES prompting abdominal exploration with partial resection of the duodenum to remove gastrinoma tumor nodules. Within 4 years of the operation, he represented with intractable hypergastrinemia despite optimal medical management with peak gastrin levels exceeding 29,000 pg/mL, in 2006. In January 2007, the patient returned to the operating room for resection of regional peripancreatic and perigastric lymph nodes and enucleation of pancreatic body and tail gastrinoma tumors. Although his gastrin level decreased to 5000 pg/mL with resultant improvement of symptoms, in less than 2 years, he developed disease progression with obstructive symptomatology from enlarging gastric carcinoids and rising gastrin levels. In May of 2008, he underwent pancreaticoduodenectomy and near-total gastrectomy. Since June of 2008, the patient shows no demonstrable progression of disease and remains asymptomatic on LAR octreotide (30 mgs). Gastrin levels have been well controlled (range, 100–624 pg/mL; current 114 pg/mL).ConclusionSuccess of this procedure in our case report highlights the potential role for optimal tumor cytoreduction and LAR octreotide to control disease progression in a patient with MEN-I and Zollinger-Ellison syndrome with locally advanced gastrinoma and secondary large gastric carcinoids.

P673Moderate anti-tumor effect of the nanoliposomal anti-PCSK9 vaccine in BALB/c mice bearing colorectal cancer

Abstract Background The higher levels of low-density lipoproteins (LDL) cholesterol (LDL-C) have been reported to correlate with higher prevalence and risk of colon cancer. Proprotein convertase subtilisin/kexin 9 (PCSK9) function, through reducing protein levels of liver LDL receptor, leads to elevated levels of plasma LDL-C. Purpose Here, we evaluated anti-tumor effect of nanoliposomal anti-PCSK9 vaccine in mice bearing colon carcinoma. Methods To formulate nanoliposomal anti-PCSK9 vaccine, liposome nanoparticles prepared by lipid-film hydration method were covalently attached to immunogenic PCSK9 peptide. The liposomal vaccine formulation was adsorbed to Alum adjuvant (L-IFPTA+) and injected subcutaneously four times with a bi-weekly interval in BALB/c mice. Two weeks after the last immunization, the vaccinated and unvaccinated mice were subcutaneously inoculated with CT26 colon cancer cells into the right flank. After tumor mass was palpable (approximately 10 mm3), the mice were randomly divided into three groups and involved to different treatments: (1) PBS (untreated control), (2) vaccine group, and (3) Doxil®(positive control) group which involved unvaccinated tumor-bearing mice who received Doxil®. To study therapeutic efficacy, mouse body weight, tumor size, and survival were monitored in a 3-day interval for 50 days. Results The nanoliposomal anti-PCSK9vaccine could efficiently induce specific antibodies against PCSK9 in BALB/c mice, and thereby reduce plasma level and function of PCSK9. Tumor size in the vaccinated mice was significantly lower than in Doxil and the control mice. Tumor size analysis revealed that time to reach endpoint (TTE) of the vaccine group was slightly but not significantly higher than that of Doxil and the control groups. The vaccinated mice survived slightly but not significantly longer than Doxil and the control mice. The vaccinated mice's life was prolonged by 24.4% as compared with the control mice, while it was increased by 9.8% in Doxil group (see Figure below). Conclusions Our findings declare that the nanoliposomal anti-PCSK9vaccine not only have no harmful effects, but also can mildly reduce tumor growth, and enhance live span and survival in mice bearing colon cancer.

Operative resection in early stage pancreatic neuroendocrine tumors in the United States: Are we over- or undertreating patients?

BackgroundMany current guidelines recommend nonoperative management for pancreatic neuroendocrine tumors <2 cm. The objective of this study was to evaluate the utilization and outcomes of resection for these pancreatic neuroendocrine tumors in the United States. MethodsUsing the National Cancer Database (2004–2014), 3,243 cases of T1 (≤2.0 cm) pancreatic neuroendocrine tumors were identified. Additional patient and tumor characteristics were examined. Multivariate models were used to identify factors that predicted resection and to assess patient survival after resection. Results75% of pancreatic neuroendocrine tumors measuring 0 to 1.0 cm and 80% of pancreatic neuroendocrine tumors measuring >1.0 and ≤2.0 cm were resected. Eighty-four pancreatic neuroendocrine tumors were functional, of which 82% were resected. Variables influencing resection included positive lymph nodes, tumor in body or tail of pancreas, well or moderately differentiated tumors, and resection at academic medical centers (odds ratio 1.5–4.9). When controlling for other variables, patients with pancreatic neuroendocrine tumors 1 to 2 cm who underwent resection had a prolonged 5-year survival rate (hazard ratio 0.51, confidence interval 0.34–0.75) when compared with those who did not undergo resection. This survival benefit of resection was not found for pancreatic neuroendocrine tumors 0 to 1 cm (hazard ratio = 0.63, confidence interval 0.36–1.11). ConclusionsContrary to many current recommendations, most patients with pancreatic neuroendocrine tumors ≤2.0 cm undergo surgical resection in the United States. A survival benefit was found for resection of pancreatic neuroendocrine tumors 1 to 2 cm, suggesting that current recommendations should perhaps be revised.

Surgical approach to solid pseudopapillary neoplasms of the proximal pancreas: minimally invasive vs. open

BackgroundSolid pseudopapillary neoplasms (SPN) of the pancreas are rare pancreatic neoplasms where complete resection is the cornerstone in management. It has been demonstrated in previous studies that minimally invasive surgical approaches are effective management options in treating SPNs of the distal pancreas. The purpose of this study is to evaluate the feasibility of minimally invasive surgery in treating SPNs of the uncinate, head, and neck of the pancreas.MethodsData from 2005 to 2017 at Severance Hospital of the Yonsei University Health systems in Seoul, South Korea, were retrospectively collected for 25 patients who were diagnosed with SPN of the uncinate, head, and neck of the pancreas and who underwent curative resection. Three groups of patients were considered, depending on the year of surgery, in order to determine trends in the surgical management of SPN. The patients were also divided into two groups corresponding to the type of operation done (minimally invasive surgery vs. open surgery). Perioperative patient data, including age, gender, body mass index (BMI), tumor size, and operation done, were compared and analyzed statistically. Long-term nutritional effects were measured using the Controlling Nutritional Status (CONUT) scoring system.ResultsThere were no statistically significant differences in age, gender, BMI, symptomatic presentation, operation type, tumor size, and tumor stage between the three time periods. In comparing between minimally invasive and open surgery, there were no statistically significant differences in age, gender, symptomatic presentation, BMI, tumor size, preoperative stage, type of operation, operation time, pancreatic duct size, post-operative pancreatic fistula (POPF) grade, death associated with disease, recurrence, pathological parameters, and change in CONUT score. There was a significant difference in tumor size (4.5 ± 1.8 vs. 2.6 ± 1.0 cm, p = 0.004), blood loss (664.2 ± 512.4 vs. 277.7 ± 250.8 mL, p = 0.024), need to transfuse (33% vs. 0%, p = 0.023), hospital length of stay (27.4 ± 15.3 vs. 11.5 ± 5.3 days, p = 0.002), and complication rate (75% vs. 30.8%, p = 0.027) between the two groups.ConclusionsIn appropriately selected patients with SPNs of the uncinate, head, and neck of the pancreas, a minimally invasive surgical approach offers at least equal oncologic and nutritional outcomes, while demonstrating decreased complications and decreased hospital length of stay compared with that of an open surgical approach.

Сlinical case of pancreatic cancer

Description of a rare case of pancreas body tumor, which was grown into celiac trunk, is presented. The patient was saved due toanftomy of right hepatic artery, which was a branch of superior mesenteric artery.&#x0D; Patient Z.V, 60 years old, came to the clinic with such complaints as pain, heaviness in abdomen and waist area,weakness.4–5 cm tumor of pancreas body was detectedduring surgery. The tumor had grown into celiac trunk and into left adrenal gland.&#x0D; The friable tissue of hepato-duodenal ligament was dissected duringthe surgery.Thesurgeons mobilized duodenum usingKoxertechnique. As a result of this manipulation, the followingblood vesselswere visualized:inferior vena cava and abdominal aorta, celiac trunk, superior mesentericartery. Surgical team opened ligament of Treitz and excisedpancreas body2.5 cm away from thetumor proximally. The stump was sewed with “mattress stich”, celiac trunk was sectioned and entangled, surgeons also dissected common hepatic artery. After section they checked blood supply of liver. The pressure of blood flowing from gastro-duodenal and pancreato-duodenal artery was enough for providing normal blood flow in the left hepatic artery.&#x0D; Morphological result of the excisedtissue — Ductal adenocarcinoma (No 672).&#x0D; The patient’sstate was satisfactory when he left the clinic. He underwent medical check-up three times next year. He feels well, his state of health is normal. Patient is capable of working.&#x0D; This case is interesting due to the anatomy of right hepatic artery (which was a branch of superior mesenteric artery) that saved patient’s life.

Abstract 377: Anti-tumor effects in combination with PARP inhibitor and DNMT inhibitor in ovarian cancer

Abstract Objective: Olaparib is one of the first PARP inhibitors and has been used for maintenance therapy in BRCA-mutant patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. However, there are some results of failure to show impressive clinical benefit with PARP inhibitor only. So, new strategies to maximize the efficacy for using these agents were developed. DNA-demethylating agents, inhibitors of DNA methylation and DNA methyltransferases(DNMTs), increase PARP1 tightly bound into chromatin in acute myeloid leukemia (AML) and breast cancer cells. The purpose of this study is to investigate the anti-cancer effect of combination therapy, olaparib with DNA demethylating agents(5-azacytidine) in ovarian cancer cell models including in vitro and in vivo - cell line xenografts and patient-derived tumor xenografts (PDX) - experiments. Methods: In vitro experiments, we treated olaparib only, 5-azacytidine only, and combination with olaparib and 5-azacytidine in ovarian cancer cell lines (A2780, SKOV3ip1, HeyA8) to evaluate the effect on cell proliferation using MTT assay. To check the human active caspase3, MMP2, and MMP9 level and the apoptosis according to each treatment, we performed the Western blot, ELISA, and apoptosis assay in ovarian cancer cell line. With wound-healing assay and migration assay, invasive ability of cancer cell was evaluated and compared after few hours of treatment with inhibitors. In addition, in vivo therapy experiments for this co-treatment in established cell line xenografts and PDX models of epithelial ovarian cancer were done. For cell line xenografts, A2780 were injected into the peritoneal cavity of mice. For the PDX model, surgical patient tumor specimens (less than 2-3mm) implanted into the subrenal capsule of left kidney and propagated by serial transplantation. We recorded body weight, tumor weight, and number of tumor nodules. Results: Both olaparib and 5-azacytidine inhibited the cell survival and increased the apoptosis in ovarian cancer cells. In this study, combination treatment of cells with olaparib and 5-azacytidine significantly inhibited the cell growth and increased the apoptosis compared to the single agent treatment in ovarian cancer cells. In in vivo experiments, combination treatment with olaparib and 5-azacytidine significantly decreased weight and nodule numbers of tumor in cell-line xenograft models with A2780 cells and PDX model compared with control, olaparib alone, or 5-azacytidine alone group. Conclusions: We found that combination treatment with olaparib and DNA-demethylating agent (5-azacytidine) has synergetic effect to attack ovarian cancer cells compared with control or single agent treatment through in vitro and in vivo tests. Citation Format: Jeong-Won Lee, Soo Young Jeong, Ji Yoon Ryu, Yoo-Young Lee, ESUN Paik. Anti-tumor effects in combination with PARP inhibitor and DNMT inhibitor in 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 377.

Efficacy analysis of Da Vinci robotic and laparoscopic distal gastrectomy for gastric cancer using propensity score matching

Objective To investigate the clinical efficacy of Da Vinci robotic and laparoscopic distal gastrectomy for gastric cancer. Methods The propensity score matching and retrospective cohort study was conducted. The clinicopathological data of 171 patients with gastric cancer who were admitted to the First Affiliated Hospital of Nanchang University from January 2015 to October 2016 were collected. There were 110 males and 61 females, aged from 38 to 81 years, with a median age of 57 years. Of 171 patients, 70 undergoing Da Vinci robotic distal gastrectomy for gastric cancer and 101 undergoing laparoscopic distal gastrectomy were allocated into the robotic group and laparoscopic group, respectively. Observation indicators: (1) the propensity score matching conditions and comparison of general data between the two groups after the propensity score matching; (2) intraoperative and postoperative situations; (3) situations of pathological examination; (4) follow-up. Patients were followed up by outpatient examination and telephone interview to detect severe complications and survival after discharge up to October 2018. The overall survival time was from the operation data to end of follow-up or time of death. The propensity score matching was used to perform 1∶1 matching by Empower Stats. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was done using the t test. Measurement data with skewed distribution were represented as M (range), and comparison between groups was done using the Mann-Whitney U test. Count data were represented as absolute number, and comparison between groups was analyzed using the chi-square test and comparison of ordinal data between groups was analyzed using the Mann-Whitney U test. The survival rate and curve were respectively calculated and drawn by the Kaplan-Meier method, and Log-rank test was used for survival analysis. Results (1) The propensity score matching conditions and comparison of general data between the two groups after the propensity score matching: 124 of 171 patients had successful matching, including 62 in each group. The body mass index (BMI) and tumor diameter before matching were (24.2±2.4)kg/m2 and (50±13)mm in the robotic group, (25.1±2.1)kg/m2 and (45±14)mm in the laparoscopic group, showing statistically significant differences between the two groups (t=-2.676, 2.045, P 0.05). (2) Intraoperative and postoperative situations: the total operation time, volume of intraoperative blood loss, level of C-reactive protein at day 1 postoperatively, level of C-reactive protein at day 3 postoperatively, volume of totally abdominal drainage were (147±13)minutes, (115±12)mL, (52.2±7.2)mg/L, (33.7±11.9)mg/L, 353.5 mL (range, 267.0-1 350.0 mL) in the robotic group, and (140±12)minutes, (131±12)mL, (58.2±7.4)mg/L, (41.1±16.9)mg/L, 397.0 mL (range, 255.0-1 600.0 mL) in the laparoscopic group, respectively, showing statistically significant differences in the above indexes between the two groups (t=3.163, -7.814, -4.631, -2.840, Z=-4.351, P 0.05). Conclusions Compared with laparoscopic surgery, Da Vinci robotic distal gastrectomy for gastric cancer has advantages in postoperative recovery and minimally invasion. There are similar 2-year overall survival rates in the two groups. Key words: Gastric neoplasms; Gastric cancer; Da Vinci robotic surgery system; Laparoscopy; Propensity score matching; Clinical efficacy

Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC).

496 Background: Sym004 consists of two anti-EGFR monoclonal antibodies (futuximab and modotuximab) directed against non-overlapping epitopes in the EGFR domain III. Sym004 induces rapid and efficient removal of the EGFR from the cancer cell surface by triggering EGFR internalization and degradation and has shown promising efficacy in mCRC patients. Based upon a post-hoc analysis of a Phase 2 study, a Phase 3 trial in genomically selected mCRC patients is in preparation. Methods: The aim was to establish a popPK model for Sym004 in order to i) evaluate impact of covariates (intrinsic and extrinsic factors) on Sym004 exposure and ii) provide exposure metrics for a PK/PD analysis. Sym004 serum concentrations were obtained from 330 patients with mCRC (n = 247) or advanced solid tumors (studies Sym004-01, Sym004-02, Sym004-05 and Sym004-06). Sym004 (0.4-18 mg/kg) was dosed by i.v. infusion weekly or every 2nd week, or as a 9 mg/kg loading dose followed by 6 mg/kg weekly (9/6 mg/kg weekly). Non-linear mixed effects modelling was done in NONMEM v7.3.0. Covariates evaluated included body weight, age, sex, race, albumin, renal function, hepatic function, tumor type and size, ECOG and previous anti-EGFR treatments. Results: The base popPK model was a 2-compartment model with linear and non-linear Michaelis-Menten-type elimination and a priori inclusion of body weight on CL, Vmax, V1 and V2. The model captured the non-linear PK well. The final covariate model retained covariates whose point estimates were outside the range of 0.8 to 1.25 and whose 90% confidence intervals did not overlap with the null value and included only body weight and albumin. Inter-individual variability was estimated for CL, Vmax and V1 and was in the range of 18-30%. Simulations were used to assess the clinical relevance of the covariates as judged by the magnitude of the change in exposure of the Phase 3 dose regimen of 9/6 mg/kg weekly. Conclusions: The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses. Clinical trial information: NCT01117428,NCT01417936,NCT02083653,NCT01955473.

Impact of obesity upon the survival of cholangiocarcinoma patients.

288 Background: Obesity is a risk factor for developing cholangiocarcinoma (CCA). However, the effect of obesity on survival of CCA is unclear. The primary aim of this study was to analyze the impact of obesity upon overall survival of CCA patients. Secondary aims were to analyze impact of obesity upon other disease characteristics such as tumor site, stage, age, sex, BMI and Ca 19-9. Methods: A total of 411 unique pts diagnosed with CCA at Mayo Clinic Florida between 2000 and 2018 were retrieved from our collective SDMS database. Variables evaluated included:demographics, Body Mass Index (BMI), AJCC stage, tumor location and Ca 19-9.A total of 185 pts had all data available pertaining to these variables. We further restricted the analysis to pts with intrahepatic CCA classified BMI as per CDC criteria normal (18.5-25kg/m2), overweight (25-29.9kg/m2) and obese (≥30 kg/m2), thus leaving a total of 152 pts. Continuous and categorical variables were compared across BMI groups using Chi-squared or Fisher’s exact test. Overall survival rates after diagnosis at 1, 2 and 3 years were estimated using Kaplan-Meier method. Results: Among 152 pts included in the study, 28% were normal weight, 40% were overweight and 32% were obese. The overall survival rate at 1, 2 and 3 years for normal weight pts with all stages combined was 54.1%, 35%, and 30.7%, respectively. The overall survival rate at 1, 2 and 3 years for overweight pts with all stages combined was 59.7 %, 32.6%, and 25.4%, respectively. The overall survival rate at 1, 2 and 3 years for obese pts with all stages combined was 63.9%, 37.6%, and 26.7%, respectively(p = 0.8766). Multivariate analysis demonstrated is no significant difference in overall survival for obese pts compared to normal or overweight pts.(Table to be shown) However it showed, gender and Ca19-9 were statistically significant predictors of overall survival, with males and pts with Ca19-9≥100 doing worse (HR1.65 (CI = 1.05, 2.61, p = 0.031) and HR 2.31 (CI = 1.49, 3.59, p = &lt; 0.01), respectively). Conclusions: BMI did not make a significant impact on the overall survival, though there may be a trend toward worse OS for ptswith higher BMI. A larger, stage focused evaluation is warranted for further exploration of this trend.

Efficacy analysis of neoadjuvant chemoradiotherapy combined with total pelvic exenteration in the treatment of primary T4b rectal cancer

To investigate the value of neoadjuvant chemoradiotherapy (nCRT) combined with total pelvic exenteration (TPE) in the treatment of primary T4b rectal cancer. A retrospective cohort study was conducted to analyze the clinicopathological data of 31 patients with primary T4b rectal cancer who underwent TPE from January 2008 to December 2015 at Peking University First Hospital. preoperative clinical stage (cTNM) was defined as cT4b primary rectal cancer with only front wall Invasion; the lower edge of tumor was within 10 cm from the anal margin; TPE was performed; R0 resection was confirmed by pathology. Patients with recurrent rectal cancer, distant metastasis, and undergoing TPE for non-rectal tumors were excluded. Patients were divided into nCRT group and non-nCRT group according to whether receiving nCRT before surgery. The nCRT group received long course radiotherapy (total dose 50 Gy in 25 daily fractions) with concomitant chemotherapy (Capecitabine), and the surgery was performed 6-8 weeks after the neoadjuvant chemoradiation, while the non-nCRT group received surgery directly. The intraoperative, postoperative and pathological conditions and local recurrence were compared between the two groups. The survival curves were drawn by Kaplan-Meier method and the survival of two groups were compared. A total of 31 patients were enrolled, including 13 patients in the nCRT group and 18 patients in the non-nCRT group. The baseline data, such as age, duration of disease, preoperative basic disease, body mass index, smoking rate, and tumor distance from the anal margin, were not significantly different between the two groups (all P>0.05). In the nCRT group and non-nCRT group respectively, the ratio of anal preservation was 30.8%(4/13) and 38.9%(7/18) (P=0.468), the median intraoperative blood loss was 1 000 ml and 800 ml (P=0.644), the operation time was (531.7±137.2) minutes and (498.0±90.1) minutes (P=0.703), the median hospital stay was 18 days and 14 days (P=0.400), the morbidity of complications within 30 days after surgery was 23.1%(3/13) and 38.9%(7/18)(P=0.452), the incidence of postoperative abdominal abscess was 15.4%(2/13) and 0 (P=0.168), the proportion of secondary surgery was 7.7%(1/13) and 11.1%(2/18)(P=1.000), whose differences were not significantly different. The proportion of postoperative pathological pT4b in whole group was 58.1%(18/31), including 53.8%(7/13) in nCRT group and 61.1%(11/18) in non-nCRT group, which was not significantly different between the two groups (P=0.691). The number of harvested lymph node in nCRT group was 13.5±5.9, which was significantly less than 23.0±11.8 in non-nCRT group (P=0.013). There was no pathological complete remission (ypCR) case in nCRT group, and among 13 patients, tumor regression grade (TRG) of 2, 3, 4, and 5 was in 1 case (7.7%), 6 cases (46.2%), 5 cases(38.5%), and 1 case (7.7%), respectively. The median follow-up time was 33 (2 to 115) months, and the follow-up rate was 93.5%(29/31). One case was lost in both the nCRT group and non-nCRT group. The 3-year disease-free survival rate was 43.5% in pooled data, and was 43.6% and 43.3% in nCRT group and non-CRT group respectively without significant difference (P=0.833). The 3-year overall survival rate was 51.1% in pooled data, and was 45.7% and 54.7% in nCRT group and non-nCRT group respectively without significant difference (P=0.653).The local recurrence rate of nCRT and non-nCRT groups was 8.3%(1/12) and 5.9%(1/17) respectively, and the distant metastasis rate was 50.0%(6/12) and 41.2%(7/17) respectively, whose differences were not statistically significant as well (P=1.000 and P=0.865, respectively). For primary T4b rectal cancer which can achieve R0 resection through total pelvic exenteration, neoadjuvant chemoradiotherapy has not been demonstrated any advantage in tumor regression, reducing local recurrence, or improving survival, and may increase postoperative complications.

Is Routine Splenectomy Justified for All Left-Sided Pancreatic Cancers? Histological Reappraisal of Splenic Hilar Lymphadenectomy.

Although splenectomy is recommended during resection for left-sided resectable pancreatic ductal adenocarcinoma (PDAC) to perform lymphadenectomy of station10 (splenic hilum), no level I evidence justifies this procedure. This study aims to evaluate the rate of lymph node (LN) and contiguous involvement of the splenic hilum in resectable distal PDAC. We retrospectively reviewed all patients who underwent splenopancreatectomy for PDAC in the past 10years. Station10 LN were routinely isolated, and all corresponding microscopic slides were reinterpreted by a pathologist. The computed tomography (CT) results of patients with tumoral involvement of the spleen or splenic hilum by contiguity (TISOSH) and ≤ 10mm between the tumor and spleen on pathology were blindly reviewed by two radiologists to evaluate CT for diagnosis of TISOSH. We included 110 consecutive patients, including 104 with analyzable station 10 LN. The tumor was N+ in 58 (53%) patients. The median number of LN identified at station10 was 2.0 ± 3.0. No station10 LNs were detected in 42 (40%) patients. No patients had tumor-positive LN at station10. TISOSH was found in nine (8%) patients, and was significantly associated with tail location (p = 0.001), tumor size (p = 0.005), and multivisceral involvement (p = 0.015). For diagnosis of TISOSH, the sensitivity and specificity of CT were respectively 89% and 95% for radiologist 1 and 89% and 100% for radiologist 2. Splenic preservation during resection of distal PDAC may be an option in selected patients with body tumors and no suspected splenic or splenic hilum involvement on preoperative CT.

Relationship between the Body Mass Index and Tumor Site Postoperative Complications and Prognosis in Gastric Adenocarcinoma

The impact of BMI on survival in gastric cancer (GC) is not clear. We sought to explore the relationship between BMI and tumor site, clinicopathologic characteristics, postoperative complications, and prognosis in GC patients. Patients who underwent gastrectomy for GC between January 2011 and June 2016 formed the study cohort (n = 827). Patients were divided into three groups according to the BMI (in kg/m²): "low" (<18.5), "normal" (18.5-24.9), and "high" (≥25.0). The preoperative level of albumin and hemoglobin in the low BMI group was lower than that in the high BMI or normal BMI group (P < 0.05). The prevalence of gastric-cardia cancer in the high BMI group was significantly higher than that in the low BMI group (P = 0.001). The prevalence of gastric-antrum cancer in the high BMI group was significantly lower than that in the low BMI group (P = 0.001) and the normal BMI group (P = 0.004). The BMI of patients with gastric-cardia cancer was significantly higher than that of patients with gastric-body cancer (P = 0.018) and gastric-antrum cancer (P < 0.001). There were no significant differences among the three groups in terms of tumor size, TNM stage, depth of tumor invasion, degree of tumor differentiation, resection margin, lymph node metastasis, or postoperative complications. BMI was not an independent factor that influenced the prognosis. We found a relationship between BMI and GC site. A low BMI may be associated with a poor prognosis and a high BMI may be related to a favorable prognosis. BMI was not an independent factor that influenced GC prognosis.