Median Survival For Group Research Articles

Prognostic significance of hepatocyte growth factor in non-metastatic colorectal cancer

Hepatocyte growth factor (HGF), produced by mesenchymal cells, stimulates mitogenesis and angiogenesis in tumor cells. Tumor cells of some solid tumors do not secrete HGF. The aim of the study was to evaluate the prognostic significance of HGF expression in tumor tissue in colorectal cancer (CRC). The study included 50 patients with stage II-III colorectal cancer; they underwent radical surgical treatment, followed by adjuvant chemotherapy according to the FOLFOX/XELOX regimen. In primary tumor samples, quantitative PCR was used to assess the level of HGF expression. Statistical processing of the obtained data was carried out using STATISTICA 13.0, BioStat v.7.1., and Jamovi 1.6.8 software. The study aims to study a new marker. Comparison of characteristics in the case of non-normal distribution was carried out using the nonparametric Mann–Whitney U test. Cox and Kaplan–Meier linear regression tests were used to analyze progression-free survival. When discussing the results, we used our previously obtained data on the level of expression of TGF-β and CXCL8 in the tumor tissue. As a result of the studies, it was found that in 60% of tumor samples HGF was not expressed, but it was significantly higher than in the resection line samples. Analysis of relapse-free survival in patients with CRC according to the level of HGF expression (predicted level by proportional hazards assessment – 0.7) showed that the median survival in groups 1 (HGF expression more than 0.7) and 2 (HGF expression less than 0.7) was 23.3 and 62.9 months, respectively (long rank test p = 0.215). It was shown that the level of HGF mRNA in CRC tumors does not depend on age, stage of the disease, and sensitivity to FOLFOX/XELOX chemotherapy. The expression level is significantly reduced in tumors with a KRAS mutation and increased in those with a BRAF mutation, in poorly differentiated tumors. Using the level of HGF expression in the tumor tissue of patients with non-metastatic CRC before the start of chemotherapy to assess the prognosis of the relapse-free period is only possible in conjunction with the expression of TGF-β, CXCL8 in the tissue and the level of CEA in the blood of these patients.

A Novel Dual Kinase Inhibitor for the Treatment of Chronic Graft Vs. Host Disease

Chronic Graft vs. Host Disease (cGvHD) remains a major debilitating and potentially fatal sequelae of allogeneic hematopoietic cell transplantation. Corticosteroids remain the initial therapy of clinically significant cGvHD. Since 2017 three targeted therapies have been approved for steroid refractory cGVHD, ruxolitinib, a JAK 1/2 inhibitor, is approved post one or two previous therapies. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and belumosudil, a ROCK2 inhibitor, are both approved after two previous lines of therapy. We tested RR- RR-1752 a single digit nM dual ROCK/AURK inhibitor in a mouse model of severe cGVHD. BALB/c recipient mice were preconditioned with 7.5 Gy TBI, 8 hours later they received 10 7 T-cell depleted (TCD) C57BL/6 bone marrow cells alone (Group A, n=7) or 10 7 TCD C57Bl bone marrow cells plus 10 6 splenocytes (Groups B, n=8 and C, n=8). Beginning day 7 post cell infusion animals received either oral vehicle control (groups A and B) or vehicle with 1.0 mg/kg RR-1752 (Group C) daily. Body weight, alopecia score and eye score were monitored 3×/week through day 56 or until termination. All animals in groups B and C developed signs and symptoms of chronic graft vs. host disease. Animals in group A exhibited 20% weight loss through seven days post irradiation and cell infusion but began to recover to baseline and recovered weight to 90% of baseline. Animal weights in groups B and C dropped to less than 80% at day seven post irradiation, but only recovered to 80.38% +/- 10.18 (Group B) and 87.11% +/- 7.90 (Group C) on day 14 and then declined to 74.10% +/- 4.19 in Group B and 80.23% +/- 7.35 in Group C by day 28 (Figure 1). Animals in Group A had no significant change in eye score or alopecia. In contrast all animals in groups B and C showed signs of cGvHD. Eye showed moderate effects in Group B and mild changes in group C, while alopecia scores were moderate in both groups B and C. All animals in group A survived through day 56, median survival in group B was 16.5 days, as compared to 38 days in group C (Figure 2). In a separate study in normal mice, RR-1752 given at 1.0 mg/kg/day for 2 weeks showed no negative effects on hemoglobin, hematocrit, platelets, total WBC, or neutrophils, and only a mild decrease in lymphocytes. Using a model for cGVHD, exhibiting weight loss, alopecia, and ocular changes, we demonstrated that RR-1752 1.0 mg/kg/day slows mouse body weight loss, increases survival and shows trends to ameliorate ocular toxicity. The dose tested did not ameliorate the alopecia in the cGVHD mice. Further studies are ongoing to assess higher dose levels and dose schedule effects in the severe cGVHD mouse model. Additional studies to compare effects on cGVHD to ruxolitinib and belumosudil and in combination with those standard of care therapies need to be conducted.

Feasibility of 125I brachytherapy combined with arterial infusion chemotherapy in patients with advanced pancreatic cancer.

To evaluation the feasibility of Iodine-125 (¹²5I) brachytherapy combined with arterial infusion chemotherapy in patients with advanced pancreatic cancer. A total of 72 cases with Stage III and IV were retrospectively reviewed. 23 cases receiving 125I brachytherapy were classified as Group A. 27 cases receiving arterial infusion chemotherapy (gemcitabine + cisplatin, GP) were classified as Group B and 22 cases receiving 125I brachytherapy combined with arterial infusion chemotherapy (GP) were classified as Group C. The evaluated indications were local control rate, survival rate, carbohydrate antigen 19-9, pain relief, and Karnofsky physical scores. Analysis of Variancep, Pearson chi-square test and Kaplan-Meier curves were used for analysis. The local control rate of group A and group C was significantly higher than group B (P < .001). Pearson chi-square test showed statistical difference of the 3 groups (χ2 = 12.969, P = .044). The median survival of group A,B and C was 9 months, 6 months and 13 months, respectively. The survival time of group C was significantly higher than group B (χ2 = 5.403, P = .020). The Log rank test showed statistical difference in the survival curve of the 3 groups (χ2 = 6.501, P = .039). The difference of carbohydrate antigen 19-9 decline percentage between group B and C group was statistically significant (χ2 = 5.959, P = .015). Patients in group A and group C relieved form pain after treatment with statistically significant (P < .001). Pain relief was much more effective in patients who received 125I brachytherapy. Karnofsky physical scores after treatment were statistically higher than those before treatment in each group (P < .001). 125I brachytherapy maybe one of the effective, safe and feasible alternative treatment of advanced pancreatic cancer. ¹²5I brachytherapy combined with arterial infusion chemotherapy was effective in the treatment of advanced pancreatic cancer.

Abstract 2086: Intratumorally administrated encapsulated IL-12 (PCX12) promotes anti-tumor immune response in GL-261 murine orthotopic glioma model

Abstract Glioblastoma (GBM) is inherently immunosuppressed (cold). Short term localized controlled immune activation has been shown to increase cytotoxic T cell infiltrate, resulting in reduced tumor growth and prolonged survival (Barrett et al. 2018). We have developed an encapsulated-mouse IL-12 formulation (mPCX12), using a sustained IL-12 release platform (Egilmez et al. 2000) to facilitate short term localized immune activation in the tumor without systemic toxicity. mPCX12 elicited a sustained dose-related IL-12 release concomitant with downstream IFNγ in mouse splenocytes, demonstrating mPCX12’s biologic activity. Similar results were observed with hPCX12 in human PBMCs. In an orthotopic murine glioma model, C57B6/L mice were inoculated with 3 × 105 GL-261 glioma cells in the frontal lobe via intracranial injection with drug treatment on Day 5. Mice were randomly assigned (n=22/group) to receive a single intratumoral dose of mPCX12 at 0.5, 0.75 and 1 mg, or mrIL-12 1µg (equivalent to mPCX12 1mg), or empty shells or vehicle. In addition, lomustine (6 mg/kg, QD×5 i.p.) was also assessed. The results showed that mPCX12 treatment increased tumor IL-12 and downstream IFNγ levels in a dose dependent manner. At 1mg mPCX12, tumor IL-12 and IFNγ levels were 2069±631 and 646±8 pg/mg, respectively, on Day 3. Low levels of IL-12 and IFNγ were observed in the systemic circulation of mPCX12 and mrIL-12 groups. mPCX12 tumor IL-12 level persisted, while mrIL-12 returned to baseline by Day 7. Flowcytometric immunophenotyping of tumors showed increased cytotoxic T cells in mPCX12 treated gliomas. These increases in local cytokine levels translated into a dose-related prolongation of survival compared to the median survival in the groups treated with vehicle and empty shells (~19 days), lomustine (20 days), and mrIL-12 (37 days). mPCX12 elicited a dose-related increase in survival. For mPCX12 at 1mg, the median survival was &amp;gt;90 days. At Day 90, 41%, 45% and 55% of the animals that received doses of 0.5, 0.75 or 1mg mPCX12, respectively, were alive with median survival &amp;gt;90 days (last day of study). At the end of the study, a portion of the surviving mice subgroups were euthanized, and those animals treated with mPCX12 were tumor free. The remaining surviving mPCX12-treated animals from the 0.75 mg and 1 mg mPCX12 groups were reinoculated with 3 × 105 GL261 cells in the ipsilateral side of the brain and compared with age-matched control vehicle or empty shells. The median survival in control groups was 27 days, and all rechallenged mPCX12-treated groups survived at Day 90, demonstrating memory T cell activation. In summary, short-term controlled release of locally administered IL-12 via PCX12 resulted in turning cold tumors hot, resulting in enhanced overall survival in an orthotopic GBM model. Thus, short term controlled locally administered PCX12 warrants further investigation in GBM patients. Citation Format: Sribalaji Lakshmikanthan, Damaris Diaz, Prasad Kolli, Arunthi Thiagalingam, Paul M. Gonzales, Mario Sepulveda, Jessica Dalsing-Hernandez, Francois Lebel, John A. Barrett. Intratumorally administrated encapsulated IL-12 (PCX12) promotes anti-tumor immune response in GL-261 murine orthotopic glioma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2086.

P50.05 Natural History and Real-World Treatment Outcomes for NSCLC Patients with EGFR Exon 20 Insertion Mutation: An IASLC- ASCO CancerLinQ Study

Epidermal Growth Factor Receptor (EGFR) exon 20 insertion (ex20ins) mutations account for 2-3% all non-small cell lung cancer (NSCLC) patients. Patients with ex20 ins do not respond to standard EGFR TKI therapy. In this work, we have analyzed the characteristics, treatment patterns and outcomes in this subgroup of NSCLC patients. The ASCO CancerLinQ Discovery dataset was queried to identify patients diagnosed with NSCLC between the years 1995-2018 and with EGFR ex20ins mutations. Data were extracted on patient demographics, tumor characteristics, treatments and outcomes, and compared with Chi-square and ANOVA tests. Kaplan-Meier (KM) curves were generated for comparing overall survival with log-rank tests. All analyses were performed using Python 3.6. A total of 357 patients were eligible. Patient characteristics: median age 68 years, female 53.5%, white race 63% and black race 9%. Approximately 62% had stage 4 disease, and 30% had brain metastasis. 54% of the patients were treated with chemotherapy and 15% with immune check point inhibitors (ICI). In patients with brain metastasis, 16% were treated with ICI, 18% targeted therapy and 59% with chemotherapy. The median survival of the entire group is 23.8 months. Among patients with stage 4 disease: 51% were females, 64% white race, 37% had brain metastasis, 18% were treated with ICI, 14% targeted therapy and 60% treated with chemotherapy. In the analysis of stage 4 patients, the median survival of the group was 16.8 months. Stage 4 patients that received ICI had better survival vs. those who did not (29.1 vs. 14.7 months; p=0.01). Stage 4 patients treated with ICI and chemotherapy had better survival compared to those treated with chemotherapy alone (29.1 vs. 16.5 months, p=0.01). Stage 4 patients treated with targeted therapy had better survival compared to those that did not receive targeted therapy (20.6 vs. 16.1 months; p=0.03). Stage 4 NSCLC patients with EGFR ex20ins mutation had favorable real-world survival when treated with ICI and targeted therapy.

Pre-Clinical Activity of SN37169, a Novel Hypoxia-Activated FLT3 Inhibitor Prodrug in FLT3-Mutated AML

Activating mutations in the Fms-like tyrosine kinase 3 gene (FLT3) are the most frequently observed molecular abnormalities in AML, which lead to overexpression or constitutive activation of the tyrosine kinase. While several mechanisms of resistance to FLT3 inhibitors have been identified, commonly failure is associated with lack of complete and sustained inhibition of FLT3 tyrosine kinase activity, with dose escalation limited by toxicities. Widespread hypoxia has been shown by us and others to be prevalent within the confines of the leukemic BM space, and to limit the efficacy of standard chemotherapy (Benito et al., PLoS One 6(8):e23108, 2011). With the goal of exploiting hypoxia as a physiological target and increasing selectivity to FLT3-mutant AML blasts, we have developed SN37169, a hypoxia-activated FLT3 inhibitor pro-drug based on an analogue of the known clinical compound Quizartinib (AC220). Bioreductive trigger conjugation was performed at the final step of the synthesis to provide SN37169 as previously described (Lu et al., Tetrahedron, 69, p9130-9138, 2013). Under hypoxia, SN37169 can undergo an enzymatic one-electron reduction and then fragment selectively to release the cell permeable SN37168 effector, generating higher local concentrations of active FLT3 inhibitor SN37168 and limiting normal tissue exposures.Pulse radiolysis was first used to determine the electron affinity (E(1)) and rate of fragmentation (kfrag) of SN37169 following one-electron reduction under hypoxia. SN37169 demonstrated E (1) and kfrag parameters ideal for hypoxia-selective cellular metabolism (-449 mV, 62 s-1, respectively).We have previously reported SN37169 to selectively inhibit FLT3 auto phosphorylation in MV4-11 cell line under hypoxic but not oxic conditions, with similar potency to the parental inhibitor (Quizartinib) under normal oxygen culture conditions (Cavazos et al. ASH 2016). We then examined the hypoxia-dependent anti-leukemia activity of SN37169 in 3 primary FLT3-mutated AML samples. SN37169 exhibited hypoxia enhanced apoptosis and growth arrest, with Hypoxia Cytotoxicity Ratios (Oxic/Hypoxic IC50 ratio) of 10.2, 9.9 and 2.8 (Figure1A).To test the efficacy of SN37169 in vivo, we injected NSGS mice with genetically engineered MOLM14/luc/GFP cells. Mice were randomized to treatment groups on day 7 when engraftment was documented by bioluminescent imaging (BLI), and treated daily with either vehicle or SN37169 at 42.3mg/kg/d IP for 4 weeks. BLI demonstrated 88-99% leukemia reduction during the course of SN37169 treatment compared to vehiclel (Figure 1B and 1C). Overall survival rate in each group was estimated by the Kaplan-Meier method. The median survival for vehicle group was 25 days while for SN37169 group was 56 days (p= 0.0043) (Figure 1D).To compare the efficacy of SN37169 with that of Quizartinib in vivo, we established an AML FLT3-ITD Patient Derived Xenograft (PDX) in NSG mice. A dose of 2.5 mg/kg/day Quizartinib in mice was estimated to provide a plasma PK profile comparable to 30 mg/day Quizartinib in human subjects based on calculated total AUC exposure across species (Zarrinkar et al., Blood 114:2984-2992, 2009). Weekly human CD45 engraftment analysis in peripheral blood using flow cytometry and daily body weight change measurements has demonstrated a significantly reduced leukemia burden in SN37169 treated group compared to vehicle (p < 0.0001) and Quizartinib (p < 0.0001) treatment groups with no indication of dose related toxicity (Figure 1E and 1F). The efficacy/PD/PK study is ongoing and median survival for all groups is yet to be determined.In summary, our data indicate hypoxia-enhanced inhibition of mutant FLT3 and its selected downstream signaling, hypoxia-dependent growth arrest and apoptosis in FLT3-mutant AML cells and notable in vivo activity of a novel hypoxia-activated FLT3 inhibitor SN37169. These findings support the functional role of hypoxia in the leukemia microenvironment and implicate potential clinical utility of hypoxia-activated kinase inhibitors with the goal of increasing efficacy and reducing toxicity. [Display omitted] DisclosuresDaver:Pfizer Inc.: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Jazz: Consultancy; Incyte Corporation: Honoraria, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Immunogen: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Karyopharm: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding.

Metastatic or suspected metastatic cancer in patients 90 years of age or older: A single-institution, multi-site study

BackgroundMetastatic cancer in nonagenarians and those older is rare and understudied. Here we explored whether these patients appear to benefit from antineoplastic therapy and whether outcomes differ based on whether or not untreated patients had a histologic/cytologic confirmation of cancer. MethodsIn this single-institution, multi-site study, we reviewed 10 years of consecutive medical records of patients 90+ years of age with a histologic/cytologic cancer diagnosis and metastatic cancer or, alternatively, a presumed metastatic cancer diagnosis. ResultsSixty-eight patients are the focus with a median age of 93 years (range: 90, 103 years). Patients fell into 3 groups: 1) no tissue/cytologic cancer diagnosis and no treatment (=23); 2) tissue/cytologic diagnosis but no treatment (n = 21); and 3) cancer treatment rendered (n = 24). The median survival in groups 1,2, and 3 was 5 weeks (95% confidence interval (CI): 2, 11 weeks), 9 weeks (95% CI: 3, 23 weeks), and 60 weeks (95% CI: 38 weeks, not yet reached), respectively. For those patients in group 3 who received cancer therapy, chemotherapy, radiation, and surgery were administered in 11 (16%), 6 (9%), and 4 (6%), respectively. Fourteen received other cancer therapy: hormonal therapy (n = 6), targeted therapy (n = 6), and immunotherapy (n = 2). Only one patient experienced an adverse event that required hospitalization. ConclusionsAlthough these older patients likely received cancer treatment on a selective basis, such treatment was associated with improved survival and was well-tolerated. However, based on survival outcomes, one might question whether to put patients through a biopsy, if they have limited therapeutic options.

The usefulness of Palliative Prognostic Index in predicting the survival of patients with advanced lung cancer

BACKGROUND AND AIM: In advanced cancer patients, life expectancy is essential in making end-of-life decisions for clinicians and patients. Palliative Prognostic Index (PPI) is a prognostic tool commonly used in palliative care for prediction survival. The aim of this study is to evaluate the accuracy of PPI for predicting survival in patients with advanced lung cancer. MATERIALS AND METHODS: Patients with advanced lung cancer hospitalized in a palliative clinic were included in this retrospective study. The PPI score was calculated by the doctor on admission day. The patients were divided into three groups according to their PPI score: group A: PPI ≤4, Group B: 4 6. All patients were followed up for up to 3 months. The survival analyses were performed using the Kaplan–Meier analysis. RESULTS: There were 177 (87.2%) men for a total of 203 patients with advanced lung cancer included in the study. The overall mean age was 64.59 ± 10.87 years; 97% of the patients died during the follow-up period. Their overall median survival was 17 days. The median survival for Group A (51 days, 95% confidence interval [CI]: 39.7–62.2) was significantly longer than Group B (16 days, 95% CI: 10.4–21.5) and Group C (6 days, 95% CI: 4–7.9). For a PPI ≤4 and 6-week survival, the sensitivity and specificity were 82.5% and 75.7%, respectively. For a PPI >6 and 3-week survival, the sensitivity and specificity were 57.7% and 91.3%, respectively. CONCLUSION: The PPI is a valuable and useful prognostic tool in predicting survival time for advanced lung cancer patients in palliative care.

An iodine-125 seed strand combined with a metal stent versus a metal stent alone for obstructive jaundice caused by pancreatic ductal adenocarcinoma

PurposeThe purpose of this study was to assess the efficacy of an iodine-125 (125I) seed strand combined with a metal stent compared with a metal stent for treatment of obstructive jaundice caused by pancreatic ductal adenocarcinoma (PDAC). Methods and MaterialsA retrospective analysis was carried out of patients who were referred to Shanghai Zhongshan Hospital of Fudan University with a diagnosis of PDAC between January 1, 2010 and January 31, 2019. A total of 110 consecutive patients with obstructive jaundice caused by PDAC were divided into the iodine-125 seed strand combined with a metal stent group (Group A = 48) and the metal stent group (Group B = 62). The primary outcome was stent obstruction–free survival time, and secondary outcomes were overall survival and complications. ResultsThe median stent obstruction–free survival time was 133.0 (95% confidence interval (CI): 166.093–149.907) days, and the median overall survival was 212.0 (95% CI: 187.183–236.817) days in all patients. Median stent obstruction–free survival time was 175 days (95% CI 103.165–246.835 days) in Group A versus 120 days (95% CI 87.475–152.525 days) in Group B (p = 0.035). A lower Eastern Cooperative Oncology Group (ECOG) score (p = 0. 000) and iodine-125 seed strand combined with metal stent implantation (p = 0.008) were associated with a longer stent obstruction–free survival time. Obstruction length (p = 0.083), ECOG score (p = 0.000), and iodine-125 seeds (p = 0.037) might have potential impact on stent obstruction–free survival time and were included for multivariable analysis using the Cox proportional hazards model. Stent restenosis was observed in 18.8% (9/48) of patients in Group A and 54.8% (34/62) in Group B, respectively. There was no significant difference in median survival between Group A and Group B (p = 0.409). The median survival in Group A was 209 days (95% CI 150.750–267.250) and 202 days (95% CI 190.624–233.376) in Group B. The median survival of patients with a lower ECOG score was better than that of patients with a higher ECOG score (267 days vs 132 days, p = 0.000). The Grade 3 or 4 complications occurred in 4 (8.3%) of the 48 patients in Group A (one case of hemobilia, one case of liver abscess, two cases of choleperitonitis) and in 5 (8.1%) of the 62 patients in Group B (one case of hemobilia, two cases of liver abscess, two cases of choleperitonitis) (p = 0.972). ConclusionsImplantation of an iodine-125 seed strand combined with a metal stent provides longer obstruction-free survival time compared with a metal stent in patients with obstructive jaundice caused by PDAC. It seems reasonable to choose an iodine-125 seed strand combined with a metal stent as a treatment for these patients.

214 OESOPHAGECTOMY POST INDUCTION THERAPY: COMPLETE PATHOLOGICAL RESPONDERS VERSUS OTHERS

Abstract Induction therapy is reported to improve outcomes in patient with loco regionally advanced cancer of oesophagus; benefit is most in patient who respond to neoadjuvant therapy. This study compares outcomes between patients with complete pathological response (Group A) and others (Group B). Methods This is a retrospective analysis of prospectively maintained database of 257 patients with cancer oesophagus undergoing surgery after neoadjuvant therapy between 2009 and 2019. Parameters analysed were stage at presentation, type of induction therapy, pTNM stage, pattern of failure and overall survival. Results 209(81%) patients received chemotherapy alone and 48(19%) chemoradiation. 43(17%) patients had complete pathological response. Of the complete responders 21/209(10%) and 22/48(45.8%) patients had received chemotherapy alone and chemoradiation respectively. Majority of patients in both groups were T3/4 (Group A:93%, Group B:93.9%) and node positive (GroupA:81.4%, GroupB:85%). Median number of lymph nodal yield for Group A and Group B was 22 and 20 respectively. Three(7%) patients in Group A had local recurrence and 2(4.7%) had distant failure. The same for non responders was 34(15.9%) and 49(22.9%). The median survival for Group A is 7.03 years and Group B is 2.1 years. Conclusion The overall median survival is significantly higher for complete pathological responder as compared to partial or non responders. Despite complete pathological response some patients will have recurrences. Chemoradiation is associated with higher complete pathological response compared to chemotherapy alone.

Survival benefit of higher fraction dose delivered by three-dimensional conformal radiotherapy in hepatocellular carcinoma smaller than 10 cm in size.

Objective: Even in early-stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult tumor location. To compare the safety and efficacy of different fractions on the survival of patients with tumors smaller than 10 cm in size, hepatocellular carcinoma (HCC) patients ineligible for curative therapies were treated with three-dimensional conformal radiotherapy (3DCRT).Methods: A total of 198 HCC patients who had tumors smaller than 10 cm and were not eligible for surgical resection or local ablation therapy received 3DCRT. Participants were separated into two groups. The treatment for Group A (n=111) was a median total dose of 53 Gy with a fraction of 2.5–4.9 Gy given three times a week, while treatment for Group B (n=87) was a median total dose of 52 Gy with a fraction of 5.0–7.0 Gy given three times a week. Propensity score matching (PSM) was conducted, and after the PSM, 81 pairs of patients arose. The Kaplan–Meier method was adopted to analyze overall survival; multivariate analysis was applied to identify the prognostic factors of survival.Results: The median follow-up time was 19.7 months (ranging from 1 to 186 months). The median survival for Group A patients versus Group B patients was 14.4 versus 24.8 months (P=0.003), respectively. The overall survival rates at 1, 3, and 5 years were 57.7%, 30.6%, and 18.9% for Group A patients and 73.6%, 43.7%, and 33.3% for Group B patients, respectively (P=0.009). In addition, the results in the PSM model appeared to be similar between the two groups. After PSM, the association between four independent prognostic factors and worse overall survival was discovered as follows: tumor size (>5 cm), Child–Pugh class B, portal vein tumor thrombosis, and fraction of 2.5−4.9 Gy/fx. The two groups also shared similar toxicities.Conclusions: Higher fraction dose radiotherapy delivered by 3DCRT was effective, as it offered a survival benefit without aggravating the toxicities in patients with small- to medium-sized HCC tumors who were ineligible for curative therapies.

Effectiveness of additional resection of the invasive cancer-positive proximal bile duct margin in cases of hilar cholangiocarcinoma

Introduction: There is still debate concerning the survival benefits of additional resection of the positive proximal ductal margin in cases of hilar cholangiocarcinoma (HCCA). This retrospective study was to investigate the effectiveness of additional resection of the invasive cancer positive proximal ductal margin (PM) under different level of preoperative CA19-9. Methods: Patients who underwent hepatectomy for HCCA from 2000 to 2017 were analyzed. Surgical variables, resection margin status and length of the PM (LPM), prognostic factors, and survival were evaluated. Results: A total of 228 patients were enrolled: 175 PM(-) without additional resection (group A), 21 PM(-) resulted by additional resection (group B), and 32 final positive proximal ductal margin: PM(+) (group C). The median survival of group B (20.99 months) was not significantly different with that of group A (23.00 months; P=0.16), and both of them were significantly better than that of group C (11.60 months) even in different subgroup of pr-CA 19-9 (P< 0.05). The survival of patients with LPM>10mm was significantly better than that of patients with LPM≤10mm especially when pr-CA 19-9>150U/ml (P< 0.05). Only when LPM>10mm, the survival of group B could be comparable with group A (P>0.05). Conclusion: HCCA patients could get survive benefit from the negative PM resulted by additional resection. The survival could be comparable with that of negative PM without additional resection in HCCA patients. The LPM>10 mm is potentially more associated with the survival rather than whether additional resection of the positive PM is performed under different level of pre-CA 19-9.

Effectiveness of additional resection of the invasive cancer-positive proximal bile duct margin in cases of hilar cholangiocarcinoma.

The survival benefits of additional resection of the positive proximal ductal margin (PM) in hilar cholangiocarcinoma (HCCA) remains controversial. This retrospective study investigated the effectiveness of additional resection of the invasive cancer PM under different levels of preoperative carbohydrate antigen 19-9 (CA19-9). Patients who underwent hepatectomy for HCCA from 2000 to 2017 were analyzed. Surgical variables, resection margin status, length of the PM (LPM), prognostic factors, and survival were evaluated. A total of 228 patients were enrolled: 175 PM(-) without additional resection patients (group A), 21 PM(-) after additional resection (group B), 16 PM(+) without additional resection (group C), and 16 PM(+) after additional resection (group D). The median survival of group B (20.99 months) was similar to that of group A (23.00 months; P=0.16), and both were significantly better than those of group C (11.60 months) and D (9.50 months), especially when preoperative CA19-9>150 U/mL (P<0.05). The survival of patients with an LPM >10 mm was significantly better compared with those with an LPM ≤10 mm, especially when preoperative CA19-9 was >150 U/mL (P<0.05). Only in the LPM >10 mm group, the survival of group B was comparable with that of group A (P>0.05). HCCA patients could get a survival benefit from a negative PM resulting from additional resection. Survival could be comparable with that of negative PM without additional resection among HCCA patients. An LPM >10 mm is possibly more associated with better survival compared with whether additional resection of the positive PM is performed under different levels of preoperative CA19-9.

Can free PSA be used as a biomarker in biochemical recurrence after surgery to predict castrate resistant prostate cancer?

177 Background: PSA produced from prostate cancer (PC) cells escapes proteolytic processing, resulting in a more complexed PSA and a lower %fPSA. Higher %fpsa correlates with lower PC risk. However, the role of fPSA in biochemical recurrence (BCR) after radical prostatectomy (RP) is unknown. Methods: All patients who had BCR after RP and at least one fPSA test, were included. Patients were stratified according to the %fPSA cut-off of 0.15. Multivariable logistic regression analysis was performed to predict covariates associated with a higher %fPSA. Results: A total of 81 men with BCR were found (Table 1). Interestingly, 20% (group 1) vs. 60% (groups 2) become castrate resistant (CRPC), p&lt;0.0001 and the time to reach CRPC state was much shorter in group 2 (33.5 months) vs. group 1 (57.9 months), p=0.05. Additionally, 60% of group 2 patients vs. 32.5% of group 1 patients developed metastasis, p=0.014. Lastly, median survival of 193 months for group 2 patients with no median survival for group 1, Log Rank test p=0.023. Multivariable logistic regression analysis demonstrated that secondary Gleason score of 5 (compared to 3) and %fPSA&gt;0.15 predicted CRPC status (OR 11.63, CI 95% 1.38-97.4, p=0.024, OR 7.99, CI 95% 2-31.95, p=0.003, respectively). Conclusions: %fPSA&gt;0.15 in the setting of BCR confers a more aggressive disease, manifesting in a faster development of CRPC, metastasis and death. Our findings suggest a reversal in the significance of % fPSA values in BCR patients, and should be validated in larger cohorts. [Table: see text]

Validation of Newly Proposed Time to Transarterial Chemoembolization Progression in Intermediate-Stage Hepatocellular Carcinoma Cases

Background/Aim: Determination of failure of transarterial chemoembolization (TACE) for treatment of Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma (HCC) has become important because of the development of tyrosine kinase inhibitor (TKI) treatment. We evaluated the usefulness and efficacy of the newly proposed time to TACE progression (TTTP). Patients and Methods: From 2006 to 2016, 192 BCLC-B HCC patients [median age 72 years, male/female ratio = 149/43, Child-Pugh score 5/6/7 = 106/56/30, albumin-bilirubin (ALBI) grade 1/2 = 64/128, Kinki criteria B1/B2 = 64/128] were enrolled. TTTP was defined based on a previous report and first imaging performed 3 months after initial TACE had been used to obtain baseline images. The patients were divided into three groups according to TTTP (<5, 5-10, and ≥10 months; group I, II, and III, respectively). We evaluated the relationship between TTTP and overall survival (OS) as well as the prognostic factors for death. Results: The median number of TACE procedures was 4 (interquartile range 3-7). There was a moderate correlation between TTTP and OS (r = 0.527, 95% CI 0.416-0.622, p < 0.001). The median survival for group I (n = 78), II (n = 49), and III (n = 65) was 24.6, 34.7, and 49.5 months, respectively (group I vs. group II, p = 0.023; group I vs. group III, p < 0.001; group II vs. group III, p = 0.037; Holm's method). ALBI grade 2 (HR 1.548, 95% CI 1.004-2.388, p = 0.048), alpha-fetoprotein (>100 ng/mL) (HR 1.540, 95% CI 1.035-2.291, p = 0.033), and TTTP (<5 months) (HR 2.157, 95% CI 1.447-3.215, p < 0.001) were significant prognostic factors for death in multivariate Cox hazard analysis. Conclusion: In patients with reduced TTTP, especially <5 months, it might be difficult to improve prognosis with a repeated TACE procedures. In such cases, reconsideration of the therapeutic strategy might be needed when possible.

A prognostic index to stratify survival benefit in patients of solid tumor metastases treated with stereotactic body radiotherapy.

e21578 Background: To investigate the clinical factors related to the prognosis of solid tumor metastases treated with SBRT and to create a scoring system that stratifies survival benefit. Methods: The clinical factors and follow-up data of 404 patients with metastases from solid primary (127 liver metastases, 205 lung metastases and 72 adrenal gland metastases), treated with SBRT from 2005 to 2016, were analyzed retrospectively. The prognostic index (PI) of patients was calculated based on the results of multivariate cox regression model from liver metastases cohort and pretreatment variables included were race, gender, age, KPS, primary tumor and histology, number of metastases, status of disease outside, previous treatment at SBRT site, and interval time from diagnosis to metastases. This model then was used in lung and adrenal gland metastases cohorts. Results: Median follow-upwas 24 months for liver metastases cohort. The median survival time of liver metastases was 21.8 months. Three variables were selected from liver cohort-database training as independent prognostic index for survival benefit: age (HR =1.81, p =0.03), KPS (HR =0.72, p =0.03), number of organs with active disease outside (HR =1.68, p&lt;0.01). Patients were classified into three hazard groups with significant difference. The median survival of group 1(poor) was 8.1 months, group 2 (intermediate) reached 25 months, and group 3 (excellent) reached 39.1 months (p&lt; 0.001). This prognostic index model was also been approved effectively in lung and adrenal gland metastases cohorts, which identified patient subgroups into poor and excellent prognosis. Conclusions: The prognostic index model allows solid tumor metastases patient to stratify survival benefit based on the three predictive factors. Table 1 Survival score and groupings [Table: see text]

OPEN TECHNIQUE OF HYPERTHERMIC INTRAPERITONEAL CHEMOPERFUSION IN TREATMENT OF PERITONEAL CARCINOMATOSIS IN RATS WITH ASCITIC OVARIAN TUMOR

For the first time comparative study of open and closed techniques of hyperthermic intraperitoneal chemoperfusion (HIPEC) in terms of safety and efficacy was performed in a rat model of ascetic ovarian cancer transplanted intraperitoneally. Original device and implantation technique of the device into peritoneal cavity were developed and used in the study. All animals after tumor implantation were randomized into 4 groups: 1 - control, intraperitoneal administration of 0.5 ml of saline (n=19); 2 - closed HIPEC with cisplatin, 20 mg/ kg (n=15); 3 - open HIPEC with cisplatin, 16 mg/kg (n=16); 4 - open HIPEC with mitomycin C (n=10). In preliminary stage while working out the original open technique of HIPEC we established that it requires dose reduction for cisplatin from 20 to 16 mg/kg compared to closed technique of HIPEC. We didn't find significant difference between groups 1, 2 and 3 in terms of number of postoperative complications. According to the results of analysis of body weight changes in postoperative period open HIPEC was worse tolerated compared to close HIPEC. Median survival of rats in group 2 was 53 days which was significantly higher compared to median survival in group 2-25 days (p=0,044). Open HIPEC with mitomycin C turned out to be less effective than open HIPEC with cis-platin but equally effective compared to closed HIPEC with cisplatin. However this is preliminary result and more rats have to be included in group 4 in order to make confident conclusion. Overall open HIPEC with cisplatin in accordance with suggested technique seem to be more promising than closed HIPEC in terms of improving outcomes of patients with peritoneal carcinomatosis.

Clinical risk scores in the current era of neoadjuvant chemotherapy for colorectal liver metastases.

Clinical risk scores (CRS) within the context of neoadjuvant chemotherapy for colorectal liver metastases (CRLM) has not been validated. The predictive value of clinical risk scoring in patients administered neoadjuvant chemotherapy prior to liver surgery for CRLM is evaluated. A prospective database over a 15-year period (April 1999 to March 2014) was analysed. We identified two groups: A, neoadjuvant chemotherapy prior to CRLM surgery; and B, no neoadjuvant chemotherapy. Overall median survival in groups A and B were 36 (2-137) months and 33 (2-137) months. In group A, nodal status, size, number of metastases and carcinoembryonic antigen levels were not found to be independent predictors of overall survival (OS). However, patients with a shorter disease-free interval of less than 12 months had an increased OS (P = 0.0001). Multivariate analysis of high- and low-risk scores compared against survival in group B (P < 0.05) confirms the applicability of the scoring system in traditional settings. Traditional CRS are not a prognostic predictive tool when applied to patients receiving neoadjuvant chemotherapy for CRLM. Disease-free interval may be one independent variable for use in future risk score systems specifically developed for the neoadjuvant chemotherapy era.

Clinical risk scores in the current era of neoadjuvant chemotherapy for colorectal liver metastases

BACKGROUND Clinical risk scores (CRS) within the context of neoadjuvant chemotherapy for colorectal liver metastases (CRLM) has not been validated. The predictive value of clinical risk scoring in patients administered neoadjuvant chemotherapy prior to liver surgery for CRLM is evaluated. METHODS A prospective database over a 15-year period (April 1999 to March 2014) was analysed. We identified two groups: A, neoadjuvant chemotherapy prior to CRLM surgery; and B, no neoadjuvant chemotherapy. RESULTS Overall median survival in groups A and B were 36 (2-137) months and 33 (2-137) months. In group A, nodal status, size, number of metastases and carcinoembryonic antigen levels were not found to be independent predictors of overall survival (OS). However, patients with a shorter disease-free interval of less than 12 months had an increased OS (P = 0.0001). Multivariate analysis of high- and low-risk scores compared against survival in group B (P < 0.05) confirms the applicability of the scoring system in traditional settings. CONCLUSION Traditional CRS are not a prognostic predictive tool when applied to patients receiving neoadjuvant chemotherapy for CRLM. Disease-free interval may be one independent variable for use in future risk score systems specifically developed for the neoadjuvant chemotherapy era.

EXPRESSION OF GENES RESPONSIBLE FOR MULTIDRUG RESISTANCE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS

Background: Multidrug resistance (MDR) is a natural phenomenon in development of solid and hematologic tumors. This phenomenon significantly influences both immediate and remote outcome of treatment. In this connection, an interest arises to studying this problem in multiple myeloma (MM) patients with expressed clinical signs of tumorous progression, the main of them being an absence or loss of the response to antitumor treatment. Aim: To study the expression of messenger RNA (mRNA) of a series of MDR genes, namely MDR1, MRP1, LRP, BCRP responsible for MDR development in the bone marrow aspirate of resistant patients prior to bortezomib-containing chemotherapy. Materials and methods: Study group included 19 relapsed/refractory multiple myeloma patients. Investigation of MDR genes expression was carried out on the cells of the bone marrow mononuclear fraction containing plasmocytes. The mRNA level was analyzed by semiquantitative RT-PCR (polymerase chain reaction with reverse transcription). Patients were treated with bortezomib-containing chemotherapy hereafter. Results: mRNA expression of genes MDR1, MRP1, BCRP was revealed in all (100%) patients, and that of gene LRP – in 81% of myeloma samples. The levels of MDR genes mRNA expression were different. On this basis, two groups of patients were identified: with the levels of MDR genes expression above and beyond the average. Conclusion: 100%-expression of MDR genes (MDR1, MRP1, BCRP) mRNA was revealed in drug resistant MM patients. The median survival in group of patients with higher levels of MDR genes mRNA expression versus lower levels of MDR genes mRNA expression was statistically significant.