Stage II-IV Patients Research Articles

Survival and CNS Relapse in Patients with CD5-Positive Diffuse Large B-Cell Lymphoma: A Multi-Institutional Observational Study in Japan

Background: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is usually characterized by activated B-cell type, poor prognosis, and frequent central nervous system (CNS) relapse. A sandwich therapy of dose-adjusted (DA)-EPOCH-R combined with high-dose methotrexate (HD-MTX) (DA-EPOCH-R/HD-MTX) showed excellent efficacy in a phase II study for newly diagnosed stage II-IV CD5+ DLBCL, including 2-year (yr) overall survival (OS), progression-free survival (PFS), and CNS relapse rates of 89%, 79%, and 9%, respectively (Miyazaki K, et al. Haematologica, 2020). It has been introduced in practice in Japan; however, the current status of treatment and the prognosis in patients with CD5+ DLBCL are unclear. Methods: We retrospectively analyzed the prognosis and CNS relapse rate of consecutive patients with untreated CD5+ DLBCL who were diagnosed at 30 hospitals in Japan from January 2016 to December 2021. Patients who were diagnosed with double-/triple-hit lymphoma, those with CNS involvement at diagnosis, and those who had not received any anthracycline-containing chemotherapy with rituximab (R-chemo) were excluded. We identified risk factors for OS using Cox proportional hazards method. The outcomes in the stage II-IV patients who received DA-EPOCH-R/HD-MTX were compared with those of the phase II study. To evaluate the efficacy of CNS prophylaxis, we divided patients into four groups: HD-MTX alone, intrathecal administration of MTX alone (IT MTX), both HD-MTX and IT MTX (HD/IT MTX), and no CNS prophylaxis. Results: Among the413 enrolled patients, 20 were excluded due to ineligible diagnosis or insufficient clinical information, 18 had CNS involvement at diagnosis, and 27 did not receive R-chemo. As a result, 348 patients were eligible and showed the following features: median age, 71 yrs (range, 23-92); male sex, 54%; stage II-IV, 90%; stage III or IV, 73%; ECOG performance status (PS) > 1, 30%; > 1 extranodal site, 42%; elevated serum lactate dehydrogenase (sLDH) level, 71%; high-intermediate or high International Prognostic Index (IPI), 63%; high CNS-IPI, 41%; and B symptoms, 29%. According to Hans's criteria, the nongerminal center B-cell type accounted for 67% of the 276 cases examined. Among the 348 patients, 62 (18%) received DA-EPOCH-R/HD-MTX, and 286 (82%) were treated with other R-chemo, such as R-CHOP (n = 254). The median age was 63.5 yrs (range, 29-75) in the DA-EPOCH-R/HD-MTX group and 72 yrs (range, 23-92) in the other R-chemo group. The DA-EPOCH-R/HD-MTX group included significantly more patients aged ≤ 60 yrs ( P < 0.001), although it tended to have more patients with ECOG PS > 1 than the other R-chemo group ( P = 0.069). Patients who received IT MTX made up 16% of the DA-EPOCH-R/HD-MTX group and 31% in the other R-chemo group. HD-MTX was used in 100% of patients in the DA-EPOCH-R/HD-MTX group and 17% of patients in the other R-chemo group. Details of CNS prophylaxis were HD-MTX alone in 84 patients (24%), IT MTX alone in 70 (20%), both HD/IT MTX in 28 (8%), and no CNS prophylaxis in 166 (48%). At a median follow-up of 43 months, the 2-yr OS, PFS, and CNS relapse rates of patients with stage II-IV disease in the DA-EPOCH-R/HD-MTX group were 87% (95% CI, 73-94%), 78% (95% CI, 63-87%), and 7.3% (95% CI, 2.8-18.2%), respectively. There were no significant differences in OS or PFS between stage I and stage II-IV patients in the DA-EPOCH-R/HD-MTX group. In all 348 patients with stage I-IV, both the OS ( P = 0.044) and PFS ( P = 0.043) in the DA-EPOCH-R/HD-MTX group were longer than those in the other R-chemo group. The 2-yr OS in these groups were 89% and 78%, and their 2-yr PFS were 78% and 64%, respectively. Multivariate analysis identified elevated sLDH ( P = 0.005), > 1 extranodal involvement ( P < 0.001), no IT MTX ( P = 0.005), and no DA-EPOCH-R/HD-MTX ( P = 0.005) as independent risk factors for OS. The 2-yr CNS relapse rate was 6.5% in the DA-EPOCH-R/HD-MTX group (n = 4) and 10.0% in the other R-chemo group. There were no significant differences in the CNS relapse rate between the two groups ( P = 0.54). The 2-yr CNS relapse rates of HD-MTX, IT MTX alone, both HD/IT MTX, and no prophylaxis were 9.8%, 9.1%, 3.7% (n = 1), and 10.3%, respectively. Conclusions: Our results confirmed favorable survival in the phase II study of DA-EPOCH-R/HD-MTX in clinical settings. DA-EPOCH-R/HD-MTX and IT MTX were associated with longer OS of patients with CD5+ DLBCL in our study cohort, warranting further investigation.

P017: The role of baseline bulk and dissemination measures as predictors of progression in advanced Hodgkin lymphoma

Figure 1: Probability of progression-free survival by baseline MTV (A) and Dmax (B) Introduction: Numerous clinical and FDG-PET/CT-associated models were proposed to predict treatment failure in Hodgkin’s lymphoma (HL). Baseline quantitative FDG-PET metrics are emerging biomarkers showing promising prognostic value. We retrospectively analysed the impact of tumour bulk and dissemination as measured by assessing Metabolic Tumor Volume (MTV) and D max - the distance between the furthest lesions identified by FDG-PET/CT - on the probability of progression in HL patients in clinical stages II to IV. Methods: Baseline FDG-PET/CT data of 117 patients with newly diagnosed HL from the PLRG-11 study was analysed and MTV was assessed by manual segmentation with the volume of interest (VOI) threshold of 41%SUVmax and Dmax was calculated by measuring the diameter between centroids of VOIs with SUVmax above SUVmax of the liver located furthest apart. The Median follow-up was months. The distance was measured in 3-dimensional space using Euclidean geometry. The cut-off values of MTV and Dmax were calculated with the maximally selected rank statistic method. Results: MTV cut-off value for progression-free survival (PFS) prediction was 214 ml with PPV 0,516 and NPV of 0.848 and for Dmax was 10 cm with PPV 0.291 and NPV of 1.0. In the cohort of 69 patients with negative interim PET/CT performed post-second cycle of ABVD PFS event was reported in 0% and 17% patients with Dmax below and above 10 cm, respectively and in 6% and 36% of patients with MTV below and above threshold value of 214 ml, respectively. Conclusion: Bulk and dissemination assessments in baseline PET/CT in Hodgkin lymphoma stage II-IV patients may help identify a population of patients with an especially good prognosis.

Real-world clinical data analysis of PARPi as first-line maintenance therapy in newly diagnosed epithelial ovarian cancer patients

Objective: The real-world clinical data of patients with newly diagnosed ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) who received first-line maintenance therapy with poly adenosine diphosphate ribose polymerase inhibitor (PARPi) were retrospectively analyzed, and the prognostic factors were preliminarily explored. Methods: (1) The clinicopathological data and follow-up data of ovarian cancer patients treated with PARPi first-line maintenance therapy from August 2018 (PARPi was launched in China) to December 31, 2021 in Sichuan Cancer Hospital were collected (real-world clinical data). (2) According to the different types of PARPi, real-world clinical data were divided into olaparib group and niraparib group, which were respectively compared with the inclusion and exclusion criteria of representative domestic and foreign phase Ⅲ randomized controlled trials (RCT), including olaparib as first-line maintenance therapy for advanced ovarian cancer patients with BRCA1/2 gene mutation (SOLO-1 study), niraparib as first-line maintenance therapy (PRIMA study), and niraparib as first-line maintenance therapy for Chinese advanced ovarian cancer patients (PRIME study). (3) The prognosis of the two groups and the prognostic factors were analyzed. Results: (1) A total of 83 patients were included in this study, with a median age of 51 years (47-57 years), including 75 cases of ovarian cancer, 5 cases of fallopian tube cancer, and 3 cases of primary peritoneal cancer; 5 cases of stage Ⅰ, 9 cases of stage Ⅱ, 55 cases of stage Ⅲ, 12 cases of stage Ⅳ, and 2 cases of unknown stage; neoadjuvant chemotherapy (NACT) was performed in 40 cases and non-NACT in 43 cases; 62 cases had no visible residual lesion after surgery (R0), 9 cases had residual disease lesions <1 cm (R1), 8 cases had residual disease lesions ≥1 cm (R2), and 4 cases with unknown postoperative residual disease. Thirty-two cases had PARPi treatment interruption, 40 cases had PARPi reduction, and 1 case terminated treatment due to acute leukemia. Of the 83 patients, 35 were in the olaparib group and 48 were in the niraparib group. The proportion of patients with high-grade serous carcinoma (100% and 75%, respectively) and the proportion of BRCA mutant patients (91% and 10%, respectively) in the olaparib group were higher than those in the niraparib group (all P<0.01). (2) Compared with the inclusion and exclusion criteria of the SOLO-1 study, the olaparib group had only 60% (21/35) coincidence rate; compared with the inclusion and exclusion criteria of PRIMA and PRIME studies, the coincidence rates of niraparib group were only 31% (15/48) and 69% (33/48). The most common reasons for non-compliance were number of chemotherapy courses, histopathological type, and surgical pathological stage. (3) Of the 83 cases received first-line maintenance therapy with PARPi, the median follow-up was 15.9 months (11.3-22.9 months), the median progression-free survival (PFS) was 29.7 months (95%CI: 25.9-33.6 months), and the median overall survival was 49.8 months (95%CI: 47.4-52.2 months). Univariate analysis showed that unilateral or bilateral ovarian cancer, efficacy after platinum-containing chemotherapy, presence or absence of measurable lesions at the end of chemotherapy, and total number of chemotherapy courses were significantly associated with PFS (all P<0.05). Multivariate analysis showed that unilateral or bilateral ovarian cancer, total number of chemotherapy courses, and efficacy after platinum-containing chemotherapy were independent factors affecting PFS in stage Ⅱ-Ⅳ patients with PARPi first-line maintenance therapy (all P<0.05). Conclusions: Unilateral ovarian cancer, the total number of chemotherapy courses no more than 9, and achieving complete response after platinum-containing chemotherapy before maintenance therapy are independent influencing factors of PFS benefit in patients with PARPi first-line maintenance therapy. Due to the large differences between the patients in real clinical practice and the research subjects of phase Ⅲ RCT, the results of representative retrospective studies still have important clinical reference significance.

Cost-Effectiveness Analysis of PEG-rhG-CSF as Primary Prophylaxis to Chemotherapy-Induced Neutropenia in Women With Breast Cancer in China: Results Based on Real-World Data.

Background: Pegylated recombinant human granulocyte colony-stimulating factors (PEG-rhG-CSFs) are more commonly and widely used than recombinant human granulocyte colony-stimulating factors (rhG-CSFs) in preventing chemotherapy-induced neutropenia in patients with stage II-IV breast cancer. To reduce the financial burden on these patients, the corresponding medical insurance directory needs to be revised. Objectives: To evaluate the cost-effectiveness of PEG-rhG-CSF versus rhG-CSF in patients with stage II-IV breast cancer in central China. Methods: Two Markov models, a chemotherapy model and a post-chemotherapy model, were developed to study the effects and costs, with a time horizon of 12 weeks and 35 years, respectively. Cost and probability input data were primarily obtained from a retrospective real-world study conducted in five tertiary hospitals. Propensity score matching was adopted to overcome retrospective bias. Other parameters were extracted from literature as well as advice from clinical experts. Univariate and probabilistic sensitivity analyses were conducted. Results: In the first chemotherapy model, PEG-rhG-CSF was associated with fewer episodes of febrile neutropenia (FN) (N = 19 per 1000 patients treated), infections (N = 24 per 1000 patients treated) and deaths (N = 2 per 1000 patients treated), but higher costs (¥36 more per patient treated). The post-chemotherapy model indicated that PEG-rhG-CSF led to higher gains in quality-adjusted life years (QALYs) (11.695 versus 11.516) in comparison to rhG-CSF. Sensitivity analysis showed that the cost of PEG-rhG-CSF had the greatest impact on the incremental costs, and incremental QALYs were very sensitive to the risk of RDI <85%. The probability of PEG-rhG-CSF being cost-effective compared to rhG-CSF was 66% at the willingness to pay (WTP) thresholds of ¥72,371 per QALY gained. Conclusion: According to this economic evaluation based on real-world data, PEG-rhG-CSF may be considered as a more cost-effective strategy relative to rhG-CSF for stage II-IV breast cancer patients in central China. However, to reflect a national perspective, further evidence is needed using data from larger-scale studies.

Prognostic Factors of Colorectal Cancer: A Comparative Study on Patients With or Without Liver Metastasis

BackgroundRadical or palliative surgery with subsequent adjuvant therapy is the routine treatment for stage II/III colorectal cancer(CRC) and some stage IV CRC patients. This study aimed to clarify the prognostic clinicopathological and genetic factors for these patients.MethodsFifty-five stage II-IV CRC patients undergoing surgery and adjuvant therapy were recruited, including patients without liver metastasis(5 at stage II, 21 at stage III) and with liver metastasis(29 at stage IV). Genetic alterations of the primary cancer tissues were investigated by whole exome sequencing(WES). Patients were followed up to 1652 days(median at 788 days).ResultsThe mutational landscape of primary CRC tissue of patients with or without liver metastasis was largely similar, although the mutational frequency of TRIM77 and TCF7L2 was significantly higher in patients with liver metastasis. Several main driver gene co-mutations, such as TP53-APC, APC-KRAS, APC-FRG1, and exclusive mutations, such as TP53-CREBBP, were found in patients with liver metastasis, but not in patients without liver metastasis. No significant difference was found between the two groups in aberrant pathways. If stage II-IV patients were studied altogether, relapse status, SUPT20HL1 mutations, Amp27_21q22.3 and Del8_10q23.2 were independent risk factors(P<0.05). If patients were divided into two groups by metastatic status, surgery types and Amp6_20q13.33 were independent risk factors for patients without liver metastasis(P<0.05), while TRIM77 mutations were the only independent risk factor for patients with liver metastasis(P<0.05).ConclusionsSurgery types and Amp6_20q13.33 were independent risk factors for CRC patients without liver metastasis, and TRIM77 mutations were the independent risk factor for CRC patients with liver metastasis.

Gynecologic oncologist impact on adjuvant chemotherapy care for stage II-IV ovarian cancer patients

ObjectiveWe aim to evaluate the impact gynecologic oncologists have on ovarian cancer adjuvant chemotherapy care from their role as surgeons recommending adjuvant chemotherapy care and their role as adjuvant chemotherapy providers while considering rural-urban differences. MethodsMultivariable adjusted logistic regressions and Cox proportional hazards models were developed using a population-based, retrospective cohort of stage II-IV and unknown stage ovarian cancer patients diagnosed in Iowa, Kansas, and Missouri in 2010–2012 whose medical records were abstracted in 2017–2018. ResultsGynecologic oncologist surgeons (versus other type of surgeon) were associated with increased odds of adjuvant chemotherapy initiation (adjusted odds ratio (OR) 2.18; 95% confidence interval (CI) 1.10–4.33) and having a gynecologic oncologist adjuvant chemotherapy provider (OR 10.0; 95% CI 4.58–21.8). Independent of type of surgeon, rural patients were less likely to have a gynecologic oncologist chemotherapy provider (OR 0.52; 95% CI 0.30–0.91). Gynecologic oncologist adjuvant chemotherapy providers (versus other providers) were associated with decreased surgery-to-chemotherapy time (rural: 6 days; urban: 8 days) and increased distance to chemotherapy (rural: 22 miles; urban: 11 miles). Rural women (versus urban) traveled 38 miles farther when their chemotherapy provider was a gynecologic oncologist and 27 miles farther when it was not. ConclusionGynecologic oncologist surgeons may impact adjuvant chemotherapy initiation. Gynecologic oncologists serving as adjuvant chemotherapy providers were associated with some care benefits, such as reduced time from surgery-to-chemotherapy, and some care barriers, such as travel distance. The barriers and benefits of having a gynecologic oncologist involved in adjuvant chemotherapy care, including rural-urban differences, warrant further research in other populations.

Multidisciplinary education and lifestyle camps for CKD patients and their closest family members: effects on disease progression, self-management and psychosocial condition-a retrospective cohort study.

Multidisciplinary education including psychosocial care (MDE) may alleviate high burden of chronic kidney disease (CKD). Family support also has utmost importance, yet, MDE has rarely been provided jointly for patients and their relatives. We organized intensive, 1-week-long boarding MDE and lifestyle camps for CKD stage III-V patients and their relatives and assessed the rate of CKD progression, proportion of participants' home-based dialysis choice, transplant activity, and improvement of their coping and attitude evaluated by written narratives. Outcome was compared to 40 controls with similarly advanced CKD, under standard of care on our outpatient clinic. In 60 predialysis patients, serum creatinine 12months before participation was 281 [IQR 122] µmol/l, right before MDE 356 [IQR 141] µmol/l, 12months after MDE 388 [IQR 284] µmol/l, eGFR decreased from 18.5 [IQR 10] ml/min to 14.0 [IQR 7] ml/min and 13.0 [IQR 8] ml/min, respectively. Twelve months' changes before and after MDE differed significantly (p = 0.005 for creatinine; p = 0.003 for eGFR). Decreased progression was found in comparison to controls (p = 0.004; 0.016, respectively) as well. During follow-up, MDE patients compared to controls chose PD as dialysis modality more often (p = 0.004), and were more active in renal transplantation (p = 0.026). Based on narratives, MDE enhanced participants' disease-specific knowledge and ability for coping. It also improved sympathy, helpfulness, and the mutual responsibilities of family members. Our unique MDE programme with participation of the closest relatives enhanced the effectiveness of education and strengthened family support, which contributed to favorable CKD outcome, increased activity in home-based dialysis selection and transplant activity.

Rituximab with Dose-Adjusted EPOCH (R-DA-EPOCH) with or without Autologous Stem Cell Transplantation (ASCT) As First Line Treatment in Patients with Aggressive B-Cell Lymphoma with MYC and BCL-2 and/or BCL-6 Gene Rearrangements or Increase Copy Number

Rituximab with Dose-Adjusted EPOCH (R-DA-EPOCH) with or without Autologous Stem Cell Transplantation (ASCT) As First Line Treatment in Patients with Aggressive B-Cell Lymphoma with MYC and BCL-2 and/or BCL-6 Gene Rearrangements or Increase Copy Number

Risk factors and knowledge assessment of general public for chronic kidney disease in Taif Region, Saudi Arabia

Introduction: Chronic kidney disease (CKD) is a worldwide public health problem since the rapid increasing prevalence of relevant risk factors, like diabetes, hypertension, unhealthy diet, low to no physical activity and metabolic syndrome. The current study aimed at assessing the risk factors and the general public awareness of CKD in Taif region, Saudi Arabia. Method: We conducted a cross-sectional study during the period of September 2019 to March 2020. For risk factors assessment data regarding CKD cases were collected from the department of nephrology at AL-Hada Military hospital in Taif. An online-based questionnaire was distributed to the general public for knowledge assessment of CKD. 6th year pharmacy student at Taif University and nephrologists from the hospital were also invited to answer the questionnaire. Results: The data of 456 CKD patients with 600 non-CKD individuals were compared for assessment of the most common risk factors. 99% of participants were CKD stage III-V patients. The majority, n=371(81.57%), of the participants were &gt;50 years old. N=328(71.93%) had type 2 diabetes mellitus (Risk ratio= 2.32, CI= 2.03-2.65; Odd ratio=5.7, CI= 4.36-7.45), n=396(86.84%) had hypertension (Risk ratio =9.65,CI-7.46-12.48; Odd ratio: 66.73, CI=45.19-98.54) and n=264(57.89%) had a history of heart diseases (Risk ratio= 3.62, CI=2.96-4.42; Odd ratio= 7.22, CI= 5.42-9.62). In CKD groups, 28.07% of them had low physical activity. In contrast with the control group, only 4% had low physical activity level in their daily routine (p&lt;0.00001). In the general public (n=1419), 919 (64.7%) had poor knowledge, 273 (19.22%) had fair knowledge, and 227 respondents (16.01%) had good knowledge of CKD. Conclusion: The finding suggests that age &gt;50 years, low educational attainment, family history of CKD, diabetes, hypertension, history of kidney stone, CVD and high BMI were significantly associated with CKD progression. We also found that the majority of the general public had poor knowledge of CKD compared to pharmacy graduates and nephrologists. These findings warrant the need for the development of awareness initiatives and programs designed to increase the level of knowledge of the general public of CKD.

The Circumferential Resection Margin Is a Prognostic Predictor in Colon Cancer.

Objective: This study aimed to investigate the potential value of circumferential resection margin (CRM) in colon cancer prognostics.Summary Background Data: CRM has been extensively studied as an important prognostic factor in rectal and esophageal cancer, but not in colon cancer.Methods: Data from 6,681 CRM-positive patients and 25,908 CRM-negative patients diagnosed with colon cancer in 2010–2015 were obtained from the Surveillance, Epidemiology, and End Results database. Statistical analysis methods utilized included the chi-square test, Kaplan-Meier estimates, Cox proportional, and X-tile software analyses.Results: After propensity score matching, CRM positivity was found to be negatively related with survival (P < 0.001). X-tile software identified 0 and 30 mm as optimal cutoff values (P < 0.001) for prognosis, which was applicable only in stage II–IV patients. A 20 and 33% risk decrease were observed in patients with CRM between 0 and 30 mm [95% confidence interval (CI) = 0.76–0.84], and larger than 30 mm (95% CI = 0.62–0.71), respectively. Chemotherapy strongly benefited prognosis with a hazard ratio of 0.36 (95% CI = 0.34–0.38) for overall survival (OS). Patients with a CRM value of 0–30 mm seemed to benefit most from chemotherapy compared with other groups. CRM and number of regional lymph nodes are independent risk factors, and the latter is a good substitute for CRM in AJCC stage I patients.Conclusion: CRM positivity is a strong unfavorable survival indicator for colon cancer patients. A better outcome is expected with CRM values larger than 30 mm. This cutoff value only applied to stage II–IV patients. For stage I patients, number of regional lymph nodes is a good substitute to predict survival. Chemotherapy was another favorable prognostic factor, especially for patients with a CRM value between 0 and 30 mm.

Abstract LB-088: Exploratory multiplex tissue image analysis of the impact of heterogeneity in the microenvironment of primary colorectal cancer on apoptosis markers in patients

Abstract Apoptosis is essential for chemotherapy responses. We previously developed the mathematical models APOPTO-CELL and DR_MOMP to estimate the magnitude of tumor cells resilience to undergo and execute apoptosis in response to chemotherapy, and demonstrated that these models are prognostic markers of clinical responses in stage 3 colorectal cancer patients [Salvucci M et al., Clin Cancer Res 2017; Lindner AU et al., Gut 2018]. However, the heterogeneity of colorectal cancer tissue represents a hurdle that we have yet to overcome on our way to entirely understand differences in response and clinical outcome in patients. Quantification of protein levels as input for systems studies routinely reflects a local cell population average rather than protein levels in individual cells. In this study we aim to gain a better understanding of apoptosis resilience in tumors with respect to tumor cell heterogeneity and cell composition and local aspects of the tumor microenvironment. Two to three core slices of formalin-fixed and paraffin-embedded primary colorectal cancer tissue were collected from 165 stage II-IV patients from a previously used cohort [Salvucci M et al. 2017; Lindner AU et al. 2018]. The levels of 25 protein markers for cell type and immune status, apoptosis, metabolism and cell proliferation, as well as cell segmentation markers, were measured on TMA slides using a multiplexed tissue immunofluorescence imaging platform (Cell DIVE [Gerdes et al., Proc Natl Acad Sci USA 2013]). Batch correction between slides was performed using linear regression (using markers for regulatory T cell in patient tissues as housekeeping cells. Formalin-fixed gene deficient cells were used in parallel for antibody validation. The layout allowed us to create protein profiles for on average 13,079 (± 2,282 SD) cells per core per patient, and to categorize these as epithelial-like cells, regulatory T cells, T helper cells, cytotoxic T cells, other leukocytes and other cells. The data will be used to identify cells contributing most to the signal measured with traditional methods (such as reverse protein phase arrays) that were used to predict patients clinical response to therapy in our previous studies. Further, we will assess spatial differences in distribution and frequency of different cells and their contribution to clinical outcome in colorectal cancer patients. Specifically, we are investigating metrics to characterize the spatial features and layout found in each core in terms of textures, degree of lacunarity, neighboring cells composition and patterns of protein expression (diffuse vs. patchy) and co-expression among cell types. Further, we will characterize the degree of intra- and inter-patient spatial heterogeneity and will examine the association between the identified spatial motifs with macroscopical characteristics of the tumor and outcome. Citation Format: Andreas Urlich Lindner, Manuela Salvucci, Xanthi Stachtea, Steven Carberry, Philip D. Dunne, Anup Sood, Elizabeth McDonough, Sanghee Cho, Pierre Laurent-Puig, Sandra Van Schaeybroeck, Manuel Salto-Tellez, John F. Graf, Markus Rehm, Mark Lawler, Daniel B. Longley, Fiona Ginty Fiona, Jochen H. Prehn. Exploratory multiplex tissue image analysis of the impact of heterogeneity in the microenvironment of primary colorectal cancer on apoptosis markers in patients [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 LB-088.

Value of 18F-FDG PET/CT in the staging, interim therapeutic and prognostic evaluation of mucosa-associated lymphoid tissue lymphoma

Objective To assess the value of 18F-fluorodeoxyglucose (FDG) PET/CT in the staging, interim therapeutic and prognostic evaluation of mucosa-associated lymphoid tissue (MALT) lymphoma. Methods Thirty-six MALT lymphoma patients (20 males, 16 females; average age: 61.7 years) confirmed by pathology from January 2008 to January 2018 were retrospectively analyzed.18F-FDG PET/CT were performed before chemotherapy and radiotherapy for staging. The detective sensitivity was evaluated. The staging results of gastric MALT lymphoma and extragastric MALT lymphoma by PET/CT were compared with Fisher exact probability method. PET/CT was performed in 17 of 36 patients after 4 courses of chemotherapy, and 17 patients were divided into positive group (≥4) and negative group (<4) according to scores of Deauville 5-point scale. The progression-free survival (PFS) was evaluated using Kaplan-Meier survival analysis. Results FDG-positive lesions were found in 31 of 36 patients with the sensitivity of 86.1%(31/36). The results of PET/CT were negative in stageⅠpatients. In stageⅡ-Ⅳ patients, the results of 18F-FDG PET/CT combined with bone marrow biopsy were in accordance with the results of clinical staging. The accuracy of PET/CT in staging of gastric MALT lymphoma patients was 9/17, which was significantly lower than that of extragastric MALT lymphoma patients (17/19; P=0.025). The PFS of negative group evaluated by interim PET/CT was longer than that of positive group (χ2=4.16, P<0.05). The 2-year PFS rates of the 2 groups were (85.7±13.2)% and (27.8 ±21.3)%, respectively. The PFS of patients with low expression of Ki-67 was significantly longer than that of patients with high Ki-67 expression(χ2=4.22, P<0.05). Conclusions In stageⅡ-Ⅳ MALT patients, 18F-FDG PET/CT combined with bone marrow biopsy can improve the staging accuracy. The staging accuracy of PET/CT in extragastric MALT lymphoma is significantly higher than that of gastric MALT lymphoma. PET/CT and Ki-67 can provide effective information on the prognostic evaluation for patients with MALT lymphoma. Key words: Lymphoma, B-cell, marginal zone; Neoplasm staging; Prognosis; Positron-emission tomography; Tomography, X-ray computed; Deoxyglucose

Malignant testicular germ cell tumors in children and adolescents: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) protocol

ObjectivesWe report the results of an Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study on the treatment of testicular germ cell tumors (TGCT) with a pediatric PEB (pPEB) regimen (cisplatin 25 mg/m2 daily on days 1-4; etoposide 100 mg/m2 daily on days 1-4; bleomycin 15 mg/m2 on day 2, once per cycle). Methods and materialsMale patients under 18 years old with malignant TGCT were enrolled for a second national prospective protocol. All patients underwent orchiectomy at diagnosis. Those with Stage I received no chemotherapy; those with Stage II–III disease received three cycles of pPEB; and those with Stage IV received four cycles. After chemotherapy, resection of radiologically-evident residual disease was recommended. The main study end-points were overall survival and relapse-free survival. ResultsNinety-nine boys from 0.5 to 17.8 years old (median 15.4 years) were evaluable, and staged as follows: 58 Stage I (59%), 7 Stage II (7%), 14 Stage III (14%), and 20 Stage IV (20%). With a median follow-up of 59 months (range 4-165 months), 5-year relapse-free survival (95% CI) was 73% (65%-83%) for the whole sample, 65% (53%-79%) for Stage I patients, and 86% (75%-98%) for Stage II-IV patients. Five-year overall survival (95% CI) was 99% (97%-100%). ConclusionsWe confirmed a good prognosis for malignant TGCT in children and adolescents. Reducing the number of chemotherapy cycles for Stage II-III disease does not seem to negatively affect survival outcomes.

Gynecologic cancer in HIV-infected women: treatment and outcomes in a multi-institutional cohort.

To evaluate gynecologic cancer treatments in HIV-infected women for adherence to National Comprehensive Cancer Network (NCCN) guidelines and to describe survival by adherence to guidelines. Beyond cervical cancer, there are little data on treatment and outcomes for these women. This is a retrospective cohort study of HIV-infected women with gynecologic cancers. HIV-infected women with gynecologic cancers from 2000 to 2015 were identified at two urban, comprehensive cancer centers. Chart reviews extracted demographic, HIV, and cancer-related variables. Cancer treatment was evaluated for adherence to NCCN guidelines. Overall survival was compared between those who received NCCN adherent and nonadherent cancer care. Fifty-seven women were identified; 15 vulvar (26%), 26 cervical (46%), nine ovarian (16%), and seven endometrial (12%) cancers. Median time from HIV to cancer diagnosis was 8.5 years, and 88% of women were black. Thirty patients (53%) had stage I, and 27 (47%) had stage II-IV disease. Overall, 28 women (49%) received NCCN-adherent care; 22 of 30 stage I (73%) and six of 27 stage II-IV patients (22%). Among 29 women not receiving NCCN-adherent care, 69% were due to patient-related factors or toxicity. Among women with II-IV cancers, 48-month survival was higher in women who received NCCN-adherent care than those who did not (60 versus 28%). Most HIV-infected women with advanced gynecologic cancers did not receive NCCN-adherent care and had worse survival compared to those who did. Focus on treatment-related toxicities and patient-related barriers to cancer care are necessary in this population.

Surgical outcomes of laparoscopic distal gastrectomy compared to open distal gastrectomy: A retrospective cohort study based on a nationwide registry database in Japan.

To clarify the safety profile of laparoscopic distal gastrectomy (LDG) for gastric cancer patients, the short‐term outcome of LDG was compared to that of open distal gastrectomy (ODG) by propensity score matching using data from the Japanese National Clinical Database (NCD). We conducted a retrospective cohort study of patients undergoing distal gastrectomy between January 2012 and December 2013. Using the data for 70 346 patients registered in the NCD, incidences of mortality and morbidities were compared between LDG patients and ODG patients in the propensity score matched stage I patients (ODG: n = 14 386, LDG: n = 14 386) and stage II‐IV patients (ODG: n = 3738, LDG: n = 3738), respectively. There was no significant difference in mortality rates between LDG and ODG at all stages. Operating time was significantly longer in LDG compared to ODG, whereas blood loss and incidences of superficial surgical site infection (SSI), deep SSI, and wound dehiscence were significantly higher in ODG at all stages. Interestingly, pancreatic fistula was found significantly more often in LDG (1%) compared to ODG (0.8%) (P = .01) in stage I patients; however, it was not different in stage II‐IV patients. The length of postoperative stay was significantly longer in patients undergoing ODG compared to LDG at all stages. LDG in general practice might be a feasible therapeutic option in patients with both advanced gastric cancer and those with early gastric cancer in Japan.

Cost-Utility Analysis of Lipegfilgrastim Compared to Pegfilgrastim for the Prophylaxis of Chemotherapy-Induced Neutropenia in Patients with Stage II-IV Breast Cancer.

Background: Lipegfilgrastim (Lonquex®) has demonstrated to be non-inferior to pegfilgrastim (Neulasta®) in reducing the duration of severe neutropenia (SN) in patients with stage II−IV breast cancer. Compared to pegfilgrastim, lipegfilgrastim also demonstrated statistically significant lower time to ANC recovery in cycles 1–3, lower incidence of SN in cycle 2 and lower depth of absolute neutrophil count (ANC) nadir in cycles 2 and 3. The aim of this study was to quantify the cost utility of lipegfilgrastim compared to pegfilgrastim in stage II−IV breast cancer patients, taking the perspective of the Belgian payer over a lifetime horizon.Methods: Two Markov models were developed to track on- and post-chemotherapy related complications, including SN, febrile neutropenia (FN), chemotherapy dose delay, chemotherapy relative dose intensity of less than 85%, infection, death rates, and quality-adjusted life years (QALYs). Data on costs (2015 value) and effects were obtained from literature, national references, and complemented by a survey of clinical experts using a modified Delphi method. Both deterministic and probabilistic sensitivity analyses were carried out. Outcomes measures included costs, QALYs and life-years (LY).Results: At current equivalent price of €1,169, treatment with lipegfilgrastim was associated with overall costs of €9,845 vs. €10,208 for pegfilgrastim and overall QALYs of 13.977 vs. 13.925 for pegfilgrastim. Life expectancy was increased by 21 days (or 0.058 LY gained). The difference in costs stem from avoided infection, SN and FN cases in the lipegfilgrastim compared to the pegfilgrastim group. Similarly, the difference in QALYs was explained by the difference in the number of patients in the chemotherapy/G-CSF Markov state followed by infection and FN between lipegfilgrastim and pegfilgrastim. The probability of lipegfilgrastim to be cost-effective compared to pegfilgrastim was 68, 79, and 83% at the willingness-to-pay thresholds (WTP) of €10,000, €30,000 and €50,000 per QALY gained, respectively. At a WTP threshold of €30,000 per QALY gained, lipegfilgrastim was cost-effective up to €1,500 across all age bands and cancer stages, compared to the current price.Conclusions: Lipegfilgrastim is a cost-effective use of health care resources in patients with stage II-IV breast cancer.

Whole-Body Vibration Training During a Low Frequency Outpatient Exercise Training Program in Chronic Obstructive Pulmonary Disease Patients: A Randomized, Controlled Trial.

BackgroundThe aim of the study was to investigate whether whole-body vibration training (WBVT) can be applied beneficially within an outpatient low frequency exercise program.MethodsIn a prospective, controlled, randomized study, WBVT effectiveness and safety were investigated in COPD stage II-IV patients undergoing a 3-month training program. Participants took part in a 90-min circuit training once a week. On top patients were randomized to either perform squats with WBVT, or without (conventional training group (CTG)). Before and after the intervention, a sit-to-stand test (STST), a 6-min walk test (6-MWT), the COPD assessment test (CAT), and the chronic respiratory disease questionnaire (CRQ) were evaluated.ResultsTwenty-eight out of 55 patients completed the study (n = 12 WBTV, n = 16 CTG). The STST time remained nearly constant for the CTG (Δ -0.8 ± 3.1 s) and the WBVT (Δ 1.4 ± 3.2 s; P = 0.227), respectively. Similarly, for both WBVT and CTG, the 6-min walk distance remained unchanged (Δ 7 ± 55 m vs. 9 ± 45 m, P = 0.961). In three out of four categories, the CRQ scores showed a significant improvement within WBVT, and in one category when comparing across groups. The CAT score dropped by -0.8 ± 2.9 points within CTG and by 2.4 ± 2.7 points within WBVT (P = 0.105). There were no adverse events related to WBVT.ConclusionThe implementation of WBVT in the context of an outpatient low frequency exercise program did not significantly improve the patients’ exercise capacity. An improvement in CAT and partially in CRQ was shown within WBVT. However, regarding the high dropout rate (49%), these results must be interpreted with caution.

Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.

Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.

Abstract 507: Prediction of colorectal cancer recurrence with plasma miRNAs in the ColoCare Study

Abstract Background Colorectal cancer is the third most common cancer and third most common cause of cancer-related death in the US. Recurrence of primary tumors occurs in 10-40% of patients depending on tumor stage. Early detection of recurrence can increase the treatment options for those eligible for curative therapy, which may lead to better survival. We determined the levels of multiple different plasma miRNAs and assessed their association with clinical outcomes to identify specific miRNAs that may serve as predictors of CRC recurrence. Methods Colorectal cancer patients (age 18-80, newly diagnosed, stage I-IV) were recruited as part of the ColoCare Study in Seattle, Washington, between 2007 and 2011. Patients who had a blood sample taken &amp;gt;30 and &amp;lt;365 days after surgery and prior to any recurrence were included in the study (n = 83). Candidate miRNAs (miRNA 31, 141, 200b, 203, 16, 17-3p, 29a, 92a, 125b) were quantified using pre-designed TaqMan microRNA assays in triplicate assays. Plasma miRNA expression was normalized and expressed as copy number. Cox proportional hazards regression with robust standard errors was used to estimate hazard ratios of recurrence associated with level of each miRNA, adjusted for age, sex and tumor site and stratified by stage. No recurrences were observed in stage I patients. Statistical analyses were conducted separately for stages II-III and II-IV colorectal cancer. Results During a median of 1,067 days (33-2,254 days) follow-up after surgery, 20 recurrences were observed. In stage II-III patients, the presence of detectable circulating levels of miR-141 (HR = 4.30 [1.10-16.84]) or miR-203 (HR = 8.04 [1.39-46.4]) were associated with risk of recurrence. In stage II-IV patients, detectable miR-203 (HR = 3.52 [1.13-10.96]) was associated with recurrence, and elevated miR-29a levels were associated with greater risk of recurrence (HR: 1.80 per natural log unit, 95% CI: 1.06-3.04). Conclusion The present study identified multiple plasma miRNAs that may help to predict those patients at greatest risk of colorectal cancer recurrence. Our results require validation in order to determine the role for such plasma markers in clinical practice. Citation Format: Brandon Dickinson, Scott V. Adams, Cornelia Ulrich, Kathy Vickers, Michelle Wurscher, William M. Grady, Karen W. Makar. Prediction of colorectal cancer recurrence with plasma miRNAs in the ColoCare Study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 507.

Abstract 4924: Retrospective evaluation of a system model of the BCL2 family of proteins as a predictive and prognostic biomarker for the clinical outcome of stage II-IV colorectal cancer patients

Abstract With 1.4 million new cases every year, colorectal cancer (CRC) is the fourth most common cancer worldwide [Globocan 2012, WHO]. Despite therapeutic advances and improvements in overall care, TNM staging remains the best prognostic indicator for CRC patients’ clinical outcomes and is pivotal for deciding on use of adjuvant chemotherapy after resection of the tumour. Adjuvant chemotherapy is not recommended for many stage II patients and mostly high-risk patients receive chemotherapy. However, there is a lack of robust biomarkers for identifying patient response to chemotherapy, recurrence and mortality risk. We developed a system model of the BCL2 family of proteins (DR_MOMP) to assess the sensitivity of cells to genotoxic stress and to induce apoptosis triggered by chemotherapy. It calculates the stress dose required to induce mitochondrial outer membrane permeabilization (MOMP) based on absolute protein levels and the interaction of pro- and anti-apoptotic BCL2 family proteins. Cells predicted to require a high stress dose showed decreased cell death rates after being exposed to 5FU and Oxaliplatin. Profiles of BAK, BAX, BCL2, BCL(X)L and MCL1 were determined by Reverse Phase Protein Array (RPPA) technology in FFPE primary tumours collected from two distinct cohorts: stage III CRC patients who underwent adjuvant 5FU-based chemotherapy (n = 128), and stage II CRC patients from a completed clinical trial with patients randomised to adjuvant 5FU-based chemotherapy or observation only (n = 138). Protein profiles were inputted into DR_MOMP to determine chemotherapy sensitivity and to classify patients into high- or low risk categories. Findings were validated on the TCGA COAD cohort using both protein (RPPA) and mRNA (SeqV2 RSEM) expression data. Stage II patients classified as high-risk by DR_MOMP and randomised to observation only had approximately 2-fold increased risk of death from CRC compared to those classified as low-risk or received chemotherapy (HR 2.4; 95% CI 1.2-4.8; p-value = 0.0199). Among stage III patients treated with FOLFOX, those classified as high- versus low-risk had a more than 10-fold increased risk of death from CRC (HR 10.6; 95% CI 2.4-46.3; p-value &amp;lt; 0.0001). We validated this finding in 261 stage II-IV patients of the TCGA COAD cohort (HR 10.6; 95% CI 1.2-12.5; p-value = 0.0125). DR_MOMP predicted mortality risk independent of TNM staging and KRAS mutation status. Our system delivers a novel predictive and prognostic biomarker that could be combined with TNM staging when assessing initial risk and subsequent clinical management of CRC patients. Citation Format: Andreas U. Lindner, Manuela Salvucci, Mattia Cremona, Naser Monsefi, Sarah Curry, Clare Morgan, Alexa Resler, Robert O’Byrne, Orna Bacon, Michael Stuehler, Lorna Flanagan, Richard Wilson, Patrick G. Johnston, Manuel Salto-Tellez, Sophie Camilleri-Broët, Deborah A. McNamara, Bryan T. Hennessy, Elaine W. Kay, Pierre Laurent-Puig, Sandra Van Schaeybroeck, Jochen H.M. Prehn. Retrospective evaluation of a system model of the BCL2 family of proteins as a predictive and prognostic biomarker for the clinical outcome of stage II-IV colorectal cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4924.