Systemic Disease Control Research Articles

Prophylactic cranial irradiation or MRI surveillance for extensive stage small cell lung cancer.

The treatment paradigm for extensive stage small cell lung cancer (ES-SCLC) is evolving. Prophylactic cranial irradiation (PCI) has long been considered a component of standard treatment in patients with extensive stage disease who respond to chemotherapy. However, in the modern era of magnetic resonance imaging, the role of PCI has become an area of controversy following conflicting level I evidence. Due to conflicting data and toxicity concerns, the routine use of PCI has declined. Recent improvements in systemic disease control with the use of immunotherapy and reductions in the toxicity attributable to PCI with hippocampal avoidance and memantine have reignited the discussion. As such, we present here a narrative review of PCI with a focus on historical milestones, randomized data, risk mitigation and future directions.

297 Poster - Micro-morphological regression patterns of tumors and lymph nodes following neoadjuvant chemotherapy for breast cancer with follow-up analysis: a new scoring system with implication into practice

Background: One of the main advantages of neoadjuvant chemotherapy (NACT) for breast cancer (BC) is an early initiation of systemic control of disease. However, the effectiveness of NACT does not correlate with the result of standard micro-morphological regression (RG) analysis, thus disease is in some cases not well controlled or even progressed. The main aim was to categorize the micro-morphological markers of RG and the baseline characteristics of tumor that identify patients at high risk of NACT failure.

A Phase I Dose Escalation Study of Neoadjuvant SBRT Plus Elective Nodal Radiation with Concurrent Capecitabine for Resectable Pancreatic Cancer

The role of neoadjuvant radiation therapy for resectable pancreatic cancer is controversial. Locoregional failure is a large component of patient morbidity, with a significant proportion of patients dying with progression of local disease (Iacobuzio-Donahue CA, et al. JCO 2009). With recent advances in systemic disease control (Conroy T, et al. NEJM 2018), the role of local therapy may become increasingly important. We performed a prospective dose escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach. Patients with biopsy proven, localized cancers of the pancreatic head amenable to surgical resection were enrolled from 2014-2019. A 4+4 dose escalation design was employed delivering 5 fractions of 5, 6, and 7 Gy with concurrent capecitabine (825 mg/m2 BID). The maximum tolerated dose level was repeated for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions to regional nodes including the celiac, porta-hepatis, superior mesenteric artery/vein, and para-aortic stations. Dose limiting toxicity (DLT) was defined as any grade ≥3 non-hematologic toxicity (CTCAE v4.0) attributable to chemo-radiation occurring within 90 days of SBRT. Pathology was graded as per the College of American Pathologists exocrine pancreas template. A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. One patient withdrew from the study prior to completion of RT due to a malignant duodenal stricture. The most common chemo-radiation-related toxicity was grade 1 nausea (44%), with 2 patients (12.5%) experiencing grade 2 nausea. There were no DLTs identified, and SBRT was dose-escalated to the highest dose level of 35 Gy in 5 fractions. No patient had surgery delayed as a result of SBRT-related toxicities. Two patients developed metastatic disease prior to surgery and 1 patient had surgery aborted due to blood loss. Of patients completing planned surgery, 100% (13/13) had R0 resections. Median time from SBRT to resection was 20 days. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the elective nodal volume. Median follow up was 13 months. The most common pattern of failure was distant, with 6/16 patients developing metastatic disease. One patient died from post-operative complications that were deemed unrelated to neoadjuvant treatment at dose level 1. SBRT was safely dose-escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. Neoadjuvant hypofractionated RT for resectable pancreas cancers is a feasible approach with limited toxicity, and the phase IB recommended dose is 35 Gy in 5 fractions.

Prevention of brain metastases in human epidermal growth factor receptor 2-positive breast cancer.

For patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, treatments that could prevent or delay occurrence of brain metastases would improve outcome. Few studies were specifically designed to assess brain metastasis prevention. Most evidence derives from subgroup analyses of randomized trials. In the first-line metastatic setting, lapatinib, was not superior to trastuzumab to prevent CNS metastases as first site of relapse. Pertuzumab when added to trastuzumab and taxane significantly delay occurrence of brain metastases. In the second line setting, trastuzumab-emtansine has shown to improve overall survival of patients with brain metastases when compared with capecitabine-lapatinib, but there was no significant delay in brain metastases progression. Neratinib, has shown that it was able to delay brain metastases progression. Finally, tucatinib, has demonstrated benefit in progression-free survival and overall survival in combination with trastuzumab and capecitabine over trastuzumab and capecitabine for patients with or without brain metastases. There has been an impressive improvement of the outcome of patients with HER2-positive metastatic breast cancer, with improved control of systemic disease and delayed occurrence of CNS progression. Specific studies are needed to assess TKI for brain metastases prevention, particularly in the adjuvant setting.

Life-threatening pathogens in severe/progressive periodontitis: Focal infection risk, future periodontal practice, role of the Periodontology 2000.

Severe/progressive periodontitis is associated with cardiovascular disease, cancer, Alzheimer's disease, and dozens of other serious diseases. Herpesviruses are implicated in severe periodontitis and in specific subsets of each of the above systemic diseases. That both periodontitis and herpesviruses are linked to the same nonoral diseases is consistent with a systemic pathogenic role of periodontal herpesviruses. Effective control of periodontitis-related systemic diseases requires collaboration between dentistry and medicine. Periodontology has emerged as an important preventive medical discipline, and periodontal teaching and practice need to adjust accordingly.

Abstract LB-011: Patient-derived organoids may facilitate precision medicine in pancreatic cancer: Demonstrating feasibility in the context of a multi-center clinical trial

Abstract Background: Systemic disease control is the principle driver of prognosis in patients with pancreatic cancer (PDAC). Currently, there are no predictive biomarkers of clinical response to guide selection of an optimal treatment approach. Our work explores the logistics and feasibility of generating patient tumor-derived models to serve as biomarkers. Methods: Patients with borderline resectable or locally advanced PDAC enrolled to participate in a multi-institutional prospective, randomized, trial were eligible. Pretreatment core needle biopsies from diagnostic endoscopy were shipped via commercial post to a centralized organoid laboratory. Patient-specific organoids (PDO) were established as previously described by our group. Putative predictive biomarkers of clinical treatment response, including whole-exome sequencing (WES), RNA-sequencing, and pharmacotyping (chemotherapeutic sensitivity testing) were performed prospectively. Putative predictive biomarkers will be compared to clinical outcomes when approved by the trial's Data Safety Monitoring Board. Results: Approximately 40% (42/98) of patients participated in tissue acquisition for organoid development. Culture maturation can be described in three relevant phases: establishment, expansion, and characterization. The establishment phase describes the emergence of viable ductal organoid development in the setting of a culture being cleared of other components of the tumor microenvironment. During these first 3-5 passages, there are numerous potential pitfalls, including technical and logistical challenges. Out of 42, 26 (62%) PDOs were successfully established. Notably, the establishment phase appears to be an area of the greatest improvement, as the rates of successful establishment improve while the collaborative team builds experience. Expansion involves biomass accumulation in clean culture. Of those that succeeded in establishment, 77% (20/26) entered in expansion phase. We can currently report 15 PDOs having reached the characterization phase (WES, RNA-seq with subtyping, and/or pharmacotyping). Based on RNA expression profile, 10/14 were classified as classical and 4 as basal-like subtype. Mean time to pharmacotyping was 179 days. The PDOs showed a variable population distribution of sensitivity to standard-of-care chemotherapeutics (gemcitabine, paclitaxel, irinotecan, 5-FU, oxaliplatin). Conclusions: Developing a living organoid biobank from PDAC biopsies in a multi-center trial setting is a tractable approach in precision medicine initiatives. Amongst a collaborative team of physician scientists, the establishment phase is critical. PDOs from pre-treatment biopsies can be individually characterized within a clinically relevant time frame and unique tumor-specific ex vivo-derived therapeutic sensitivities can be assessed. Citation Format: Toni T. Seppälä, Jacquelyn W. Zimmerman, Noah Rozich, Alex Blair, Ammar Javed, John L. Cameron, William R. Burns, Jin He, David Tuveson, Christopher L. Wolfgang, David P. Ryan, Alec Kimmelman, Joseph M. Herman, Wells Messersmith, Theodore S. Hong, David T. Ting, Richard Andrew Burkhart. Patient-derived organoids may facilitate precision medicine in pancreatic cancer: Demonstrating feasibility in the context of a multi-center clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-011.

Abstract 5568: Neoadjuvant immunotherapy for solid tumors

Abstract Background Cancer surgery remains the most effective single treatment modality for curing patients with solid tumors. However, only half of all cancer patients undergo curative resection. Of those, a significant number will eventually relapse from occult metastases. Administration of therapy prior to surgery, known as neoadjuvant therapy, has revolutionized cancer surgery. It not only decreases overall tumor burden, rendering previously inoperable disease operable, but also improves survival by providing systemic disease control in patients at high risk of having microscopic distant metastases at the time of surgery. While traditional neoadjuvant therapy using conventional chemotherapy and radiation therapy has improved patient outcomes across a spectrum of solid tumors, the potential of neoadjuvant immunotherapy is currently unknown. Various immune modulating agents have achieved significant clinical success in the management of metastatic and treatment resistant cancers, yet their utility in the neoadjuvant setting remains unclear. In theory, neoadjuvant immunotherapy is particularly interesting because it utilizes the primary tumor as a rich source of antigens for T cell priming. As a result, it may be successful in eliciting an immune response where adjuvant immunotherapy treatment has failed. Here we designed a preclinical study utilizing neoadjuvant immunotherapy and demonstrate the efficacy of employing immune stimulating agents synergistically with surgical resection. Methods We used two different murine models of solid tumors – a metastatic triple negative breast carcinoma and a colorectal carcinoma to compare neoadjuvant immunotherapy, resection alone, or immunotherapy alone treatments on local and systemic disease control, and survival. We found that neoadjuvant immunotherapy offered the best survival as well as the best locoregional and metastatic disease control when compared to the other groups. In fact, in the highly aggressive and spontaneously metastatic breast carcinoma model the neoadjuvant treatment group was the only group in which a long-term surviving cohort of mice was cured. When these long-term survivors were rechallenged with the same tumor, they were immune, confirming that the treatment successfully conferred immunological memory. When exposed to a new tumor type, however, they remained susceptible, confirming the specificity of this immunologic memory. Disease control was found to be T cell dependent as depletion of either both CD4+ and CD8+, or CD8+ only T cells resulted in loss of therapeutic benefit in mice treated with neoadjuvant immunotherapy. Conclusion We found that neoadjuvant immunotherapy successfully initiated cell mediated antitumor activity both locally and systemically at an anatomically distant disease site. This resulted in improved survival in the neoadjuvant group when compared to groups receiving resection alone or immunotherapy alone. As increased options to incorporate immunotherapy in the clinic become available to clinicians, this study explores the timely and clinically important question of how immunotherapy may optimally be combined with surgical resection. The results of the study are readily translatable and may be utilized to inform establishment of neoadjuvant immunotherapy regimens for patients with early stage and locally advanced solid tumors. Citation Format: Wan Xing Hong, Idit Sagiv-Barfi, Debra Czerwinski, Ronald Levy. Neoadjuvant immunotherapy for solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5568.

Abstract 4069: Selective ablation of solid tumors using a p53-targeted FAST-LNP gene therapy

Abstract While chemotherapy is a key treatment strategy for many solid tumors, it is rarely curative as patients will eventually become resistant. In this study, we sought to develop an effective suicide gene therapy approach for solid tumors that specifically exploits their unique transcriptional activation state. The tumor suppressor p53 is frequently mutated or dysregulated in cancer, and as a result the upstream signaling pathways activating p53 transcription are strongly upregulated. RNA-seq analysis has demonstrated that p53 transcription is significantly upregulated in almost all forms of cancer. Additionally, HCT116 cells lacking functional p53 display a 6-fold increase in p53 promoter activity when compared to its wild type p53 parent cell line. To exploit this, we have developed a Fusogenix FAST-LNP formulation to deliver a p53-driven inducible suicide gene, iCasp9, to solid tumors and destroy them upon activation with small molecule dimerizer, Rapamycin. To establish a proof-of-concept, plasmid encoding iCasp9 and luciferase under control of the p53 promoter was constructed and evaluated in a panel of cancer cell lines. While LNPs administered without Rapamycin or Rapamycin administered alone had no impact on cell viability, we observed greater than 90% apoptotic cell death when both were employed in a wide range of cancer cell lines with p53 deletions or mutations, as measured using cell viability assays, imaging assays, as well as Annexin V and TUNEL flow cytometry. Induction of iCasp9 protein expression and caspase-mediated apoptosis was confirmed using Western blot. No cell death was observed in cells with intact p53 such as human umbilical vein endothelial cells or the fibroblast cell line IMR-90. Next, we assessed the efficacy of FAST-LNPs containing p53-iCasp9 in xenograft PC-3 and H1299 models of human prostate cancer and lung cancer respectively. In some experiments, tumors were implanted subcutaneously in the flanks of 30 mice and allowed to grow to 500 mm3 before treatment by intravenous doses of 100 µg LNP twice per week during continuous low dosing of Rapamycin. We observed a rapid and dramatic reduction in tumor volume averaging 87% over the following 48 hours, with durable response. Tumors in control mice continued to grow exponentially. Overall survival of mice was extended 250% in the PC-3 cohort and 300% in the H1299 cohort. Optimization of number and concentration of LNP doses should allow for long term control of both localized and systemic disease. In conclusion, we describe a novel LNP gene therapy approach for the treatment of cancer with high selectivity for tumors with dysregulated p53 transcriptional activation. This approach has the potential to provide a highly efficacious alternative to current therapies for localized and advanced solid tumors. Citation Format: Douglas Wilson Brown, Arun Raturi, Prakash Bhandari, Deborah Sosnowski, Liliya Grin, Ping Wee, Hector Vega, Jennifer Gyoba, Maryam Hejazi, Jailal Ablack, Matthew Scholz, John D. Lewis. Selective ablation of solid tumors using a p53-targeted FAST-LNP gene therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4069.

Strategy for the Practice of Spine Oncological Surgery During the Covid-19 Pandemic.

Case series. For each of the most frequent clinical scenarios, the authors reached a consensus on how should be timing and indications be optimized to reduce risk while maintaining the expected outcomes under the Covid-19 pandemics. The organization of health care has been changed by the Covid-19 pandemic with a direct impact on Spine Oncology Surgery. Emergency surgery is still a priority, but in case of spinal tumors it should be better defined which conditions require emergency treatment. An expert panel with general spine surgeons, oncological spine surgeons, and radiation oncologists was formed to analyze the most frequent scenarios in spinal musculoskeletal oncology during Covid-19 pandemics. Spine metastases can be found incidentally during follow-up or can clinically occur by increasing pain, pathologic fracture, and/or neurological symptoms. Primary spine tumors are much more rare and very rarely present with acute onset. The first step is to suspect this rare condition, to avoid to treat a primary tumor as it were a metastasis. Most complex surgery, like en bloc resection, associated with high morbidity and mortality rate for the treatment of low grade malignancy like chordoma or chondrosarcomas, if intensive care unit availability is reduced, can be best delayed some weeks, as not impacting on prognosis, due to the slow growth rate of these conditions. The currently accepted protocols for Ewing sarcoma (ES) and osteogenic sarcoma must be performed for local and systemic disease control. For ES, after the first courses of chemotherapy, radiotherapy can be selected instead of surgery, during Covid-19, to the end of the full course of chemotherapy. In immunocompromised patients, (treated by chemotherapy), it is necessary to avoid contact with affected or exposed people. Even more than during normal times, a multidisciplinary approach is mandatory to share the decision to modify a treatment strategy. 5.

OP0148 MEPOLIZUMAB FOR EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA): A RETROSPECTIVE REAL-WORLD EUROPEAN STUDY ON 142 PATIENTS

Background:Evidence on the efficacy of Mepolizumab (MEPO) in Eosinophilic Granulomatosis with Polyangiitis (EGPA) is scarce [1].Objectives:To assess the efficacy and safety of MEPO in real-life clinical practice.Methods:We retrospectively included patients diagnosed with EGPA and treated with MEPO (100 or 300 mg/month). MEPO efficacy was evaluated in the first 12 months in terms of systemic disease and asthma control. The occurrence of any adverse event (AE) was recorded.Results:142 patients were included (38% males; median age 46.4 (IQR 36.7-54.4); 110 and 32 on MEPO 100 and 300 mg/month, respectively). General, ear-nose-throat, pulmonary, and neurological symptoms significantly decreased during treatment (table 1). MEPO accounted for a significant reduction in the BVAS (figure 1) and for a steroid sparing effect (figure 2). The proportion of patients with asthma attacks decreased by 90% at 12 months compared to t0, and asthma-related emergency accesses dropped from 17.4% to 2.3%. Overall, 21.1% of patients had a non-serious AE.Table 1.Control of clinical symptomsMEPO beginning (t0)3 monthsp-value(t3 vs t0)6 monthsp-value(t6 vs t0)12 monthsp-value(t12 vs t0)N obsN=142N=135N=123N=89General symptoms40 (28.2%)17 (12.6%)<0.00119 (15.5%)<0.00113 (14.6%)0.002Cutaneous manifestations13 (9.2%)6 (4.4%)0.0085 (4.1%)0.0254 (4.5%)0.180ENT manifestations106 (74.7%)52 (38.5%)<0.00144 (35.8%)<0.00129 (32.6%)<0.001Pulmonary manifestations130 (91.6%)59 (43.7%)<0.00139 (31.7%)<0.00128 (31.5%)<0.001Cardiac manifestations6 (4.2%)2 (1.5%)0.0832 (1.6%)0.08300.157Intestinal manifestations10 (7.0%)1 (0.7%)0.0054 (3.3%)0.0593 (3.4%)0.059Renal manifestations5 (3.5%)3 (2.2%)0.41400.0461 (1.1%)0.317Neurological manifestations36 (25.4%)22 (16.3%)0.01218 (14.6%)0.00310 (11.2%)0.035Figure 1.Changes in BVASFigure 2.Steroid treatmentConclusion:MEPO effectively controlled systemic and respiratory EGPA symptoms in a large European cohort, with no major safety concerns.

AB0567 CHARACTERIZATION OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY AND MYOCARDIAL INVOLVEMENT: A MONO-CENTRIC EXPERIENCE.

Background:Idiopathic inflammatory myopathies (IIM) are immune-mediated disorders of the skeletal muscle, with dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune-mediated necrotizing myopathy (IMNM) representing major subtypes. Beyond skeletal muscle, other organs may be affected and myocardial involvement may lead to severe life-threatening complications. The exact prevalence of myocardial involvement among IIM patients and its impact on other disease characteristics remain unclear.Objectives:To investigate the prevalence of myocarditis in patients affected by IIM in and to determine whether the presence and extent of myocardial involvement identify a distinct disease phenotype.Methods:42 longitudinally followed IIM patients were routinely screened for myocardial involvement during a median [IQR] follow-up time of 4.2 [2-8.5] years. Patients with secondary causes of myocardial dysfunction were not included. Patients were considered to have myocarditis in case of:i) abnormal elevation of both circulating troponin T and troponin I,ii) signs of myocardial inflammation or necrosis/fibrosis at cardiac MRI, oriii) positive myocardial tissue histology. Demographic, clinical and serologic features of patients with myocarditis were compared to those with no sign of myocardial involvement. Moreover, we determined whether the extent of myocardial involvement based on troponin levels predicts skeletal muscle disease severity.Results:57.1% (24 of 42) of patients had myocarditis. The frequency of myocardial dysfunction was similar among patients with DM, PM, IBM or IMNM and was not related to autoantibody positivity. Myocarditis was not associated with sex or ethnicity. Patients with or without myocarditis were similar in terms of age at disease onset and extra-muscular manifestations including dysphonia, dysphagia, arthralgias or arthritis, Raynaud phenomenon or interstitial lung disease. Independent of the IIM subtype, the presence of perimysial macrophages at skeletal muscle biopsy seems to protect from myocarditis development (p=0.04). Patients with myocarditis had higher median [IQR] levels of aldolase (10.9 [7.8-15.8] vs. 5.6 [4.9-8.6], p=0.014) and creatine kinase (1785 [966-5852] vs. 685 [168-2255], p=0.04) compared to patients with no myocardial dysfunction. Among patients with myocarditis, levels of troponin I negatively correlated with manual muscle testing 8 (MMT8) score (r=-1, p=0.01), strength in biceps (r=-0.95, p=0.014) and wrist extensors (r=-0.95, p=0.014) at last visit. Troponin T and troponin I titers were similar among patients with different IIM subtypes. C-reactive protein (p<0.04) but not erythrocyte sedimentation rate was found to predict myocardial involvement.Conclusion:Our findings suggest that myocarditis is a frequent occurrence among patients with IIM and should be routinely ruled out. A more severe skeletal muscle disease is associated with an increased likelihood of myocarditis development, presumably due to higher systemic disease activity or inefficient disease control. The extent of myocardial damage faithfully reflects the severity of skeletal muscle dysfunction.

Induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases: Results of a randomized phase II A-PLUS trial.

1082 Background: Our previous study ( Clin Cancer Res. 2015;21(8):1851) demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for breast cancer (BC) patients (pts) with brain metastases (BM) progressing from WBRT. We conducted a randomized phase II study A-PLUS (NCT02185352) to test whether using BEEP as an induction therapy could enhance the efficacy of WBRT and provide systemic control. Methods: BC pts with measurable BM not suitable for surgery/radiosurgery and had not received WBRT were randomized (2:1) to experimental arm: induction BEEP for 3 cycles (~2 months [ms]) followed by WBRT or control arm: upfront WBRT. The BEEP regimen consists of bevacizumab 15 mg/kg on day 1, and etoposide 70 mg/m2/day on days 2-4, cisplatin 70 mg/m2 on day 2, followed by prophylaxis GCSF, every 21 days. After WBRT in both arms, pts received treatment of physician’s choice except BEEP until BM progression. Stratification was based on the Graded Prognostic Assessment score. Primary endpoint was brain-specific progression free survival (BS-PFS) based on RECIST 1.1, with a total of 108 pts, power of 0.8 at the 2-sided α level of 0.2. Results: Of 112 enrolled pts, 74 were in experimental arm and 38 in control arm. Baseline patient characteristics were generally balanced between arms. With median follow up of 28.7 ms, median BS-PFS was 8.1 vs. 6.5 ms ( p= 0.146; HR 0.71 [95% CI 0.44-1.13]), which met the primary endpoint (pre-defined α level of 0.2). Results of preplanned analysis included: 2-month brain-specific objective response rate of BEEP alone vs. WBRT was 41.9% vs. 52.6% ( p= 0.613); 8-month BS-PFS rate was 48.7% vs. 26.3% ( p= 0.027); median PFS was 6.4 vs. 4.7 ms ( p= 0.071; HR 0.67 [95% CI 0.43-1.04]), and extra-BM PFS was 7.9 vs. 5.0 ms ( p= 0.141; HR 0.71 [95% CI 0.46-1.12]). Median overall survival was 15.6 vs. 13.6 ms ( p= 0.855; HR 0.96 [95% CI 0.59-1.55]), with 31.6% of pts in control arm received BEEP regimen treatment after BM progression. The most common all-grade adverse events (AEs) in experimental arm were neutropenia (30.2%), nausea (27.9%), anemia (27.4%), and leukopenia (24.2%). Most AEs were mild to moderate in severity. Two pts discontinued BEEP treatment due to grade 4 nephrotoxicity and grade 3 infection, respectively. Conclusions: BEEP as induction treatment followed by WBRT for BC pts with BM may improve control of both BM and systemic disease. Further validation by a phase III study is necessary. Clinical trial information: NCT02185352 .

SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA).

4504 Background: Clinical outcomes after curative treatment of resectable PDA remain suboptimal. To assess the potential of early control of systemic disease with multiagent peri-op CTx, we conducted a prospective trial in the National Clinical Trials Network. Methods: S1505 was a randomized phase II trial of peri-op CTx (12 weeks pre-, 12 weeks post-op) with either mFOLFIRINOX (Arm 1) or Gem/nabP (Arm 2). Eligibility required confirmed tissue diagnosis of PDA, ECOG PS 0 or 1, and resectable disease per Intergroup criteria. Primary outcome was 2-year overall survival (OS), using a “pick the winner” design; for 100 eligible patients (pts), accrual up to 150 pts was planned to account for cases deemed ineligible at central radiology review. We previously presented data on eligibility (ASCO 2019 abstr 4137). Here we present the final efficacy and toxicity results for the eligible pts. Results: From 2015 to 2018, 147 pts were enrolled; there were 102 eligible pts; 55 in Arm 1; 47 in Arm 2. For Arms 1 and 2 respectively: median age, 66 (44-76) and 64 (46-76) years; males, 36 (65%) and 24 (51%); and ECOG PS 0, 34 (62%) and 31 (66%) pts. Treatment details are shown in Table. For Arm 1 and Arm 2, respectively: Two-year OS was 41.6% and 48.8%; median OS was 22.4 months and 23.6 months. Neither arm’s 2-year OS estimate was statistically significantly higher than the a priori threshold of 40% (p=0.42 in Arm 1 and p=0.12 in Arm 2). Median disease-free survival (DFS) after resection was 10.9 months in Arm 1 and 14.2 months in Arm 2 (p=0.87). Conclusions: We have demonstrated: 1) two-year OS of 41.6% (median 22.4 months) with mFOLFIRINOX and 48.8% (median 23.6 months) with Gem/nabP for all eligible pts starting treatment for resectable PDA; 2) post-resection DFS of 10.9 months and 14.2 months, respectively; 3) adequate safety and high resectability rates with peri-op CTx; 4) little evidence that either regimen improves OS compared with the historical standard. Clinical trial information: NCT02562716 . [Table: see text]

Institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases.

e14504 Background: The management of melanoma with multiple brain metastases (MBM) is complex given improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a radiotherapy technique with limited outcomes data. We report our institutional outcomes for MBM patients receiving WBRT and assess whether certain clinical factors impact prognosis. Methods: A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000-2018 treated with WBRT, with or without systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), progression free survival (PFS), intracranial failure-free survival (IFFS), and local failure-free survival (LFFS) were assessed. Data was collected on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits. Results: Of 1347 patients treated with WBRT from 2000-2018, 63 patients had melanoma. 69% of patients had ≥5 brain metastases at the time of WBRT, 68% had extracranial disease, and 71% received steroids during their overall treatment course. Most had received previous therapies and had WBRT as a last resort. Median WBRT dose was 30 Gray over 10 fractions. Median follow-up was 4.0 months. Six-month OS, PFS, IFFS, and LFFS were 52.7%, 20.4%, 52.3%, and 43%. Median OS, PFS, IFFS, and LFFS were 7.0 months, 2.2 months, 6.1 months, and 4.9 months. Performance status correlated with OS on univariate and multivariate analysis. BRAFi was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07-0.79, p = 0.019), although this was not seen on multivariate analysis. There was a 19% rate of memory deficits. Among the 46 patients with post-WBRT brain scans, 17% had radionecrosis and 28% had intralesional hemorrhage. Not all radiographically noted radiotoxicities were clinically significant, although hemorrhage decreased IFFS on both univariate and multivariate analysis. Conclusions: Outcomes for MBM patients receiving WBRT indicate that WBRT remains a worthy option to control intracranial disease. Treatment-related effects such as hemorrhage, necrosis, or cognitive changes are considerations. Median PFS and IFFS suggest that systemic disease control continues to be the greater issue. The role of WBRT should be re-evaluated in the modern era, which features advanced imaging detection ability, newer systemic agents, and improved steroid avoidance strategies.

Cohort 1 results of a phase I study of autolytic immunotherapy of metastatic neuroendocrine neoplasms using intralesional rose bengal disodium.

e16694 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed, especially when available options have been exhausted. Intralesional (IL) rose bengal disodium (PV-10), an autolytic immunotherapy under development for solid tumors, is being investigated as a potential option for treatment-refractory patients (pts) with hepatic metastases. Methods: This phase 1 study is evaluating the safety, tolerability and objective response resulting from percutaneous administration of PV-10 in 12 pts with progressive mNEN refractory to SSA and PPRT; pts must have at least one injectable hepatic lesion (1.0-3.9 cm in longest diameter) not amenable to resection or other potentially curative therapy. In Cohort 1 (n = 6) pts received PV-10 to a single hepatic lesion per treatment cycle, and could receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. The primary endpoint is safety. Secondary endpoints include objective response rate assessed by independent review of contrast enhanced CT and by 68Ga-DOTATATE PET. Results: Cohort 1 has fully enrolled, with 4 of 6 pts male, median age 65 yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1. NET grade: Gd1 = 5, Gd2 = 1. All pts had progressed on prior SSA and PRRT. Median baseline CgA was 645 (range 30-2819). One pt received 4 PV-10 treatment cycles, 1 received 2 cycles, and 4 received a single cycle. Toxicity was acceptable, including transient pain post procedure, carcinoid flare and nausea. A partial response of injected lesions was observed in 50% of pts (injected lesion progression in 1 pt), with an overall response of stable disease achieved in 84% of pts by RECIST 1.1 (progressive disease in 1 pt). Progression free survival (PFS) was not reached by CT (range 2.4-25.3+ months), and was 6.1 months by PET. Median overall survival (OS) was ≥22.5 months, with three subjects alive at the data cut-off of Jan 2020 (range 18.1-33.8 months). Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local response of injected tumors and prolonged systemic disease control in some pts. Enrolment to Cohort 2 is nearing completion where an additional 6 pts may receive injection of multiple lesions per treatment cycle. Clinical trial information: NCT00986661 .

Clinical Outcomes of Stereotactic Body Radiotherapy With Immediate Versus Delayed Hormone Therapy in Men With Oligometastatic Recurrence of Prostate Cancer

AimsStereotactic body radiotherapy (SBRT) with the delayed option of androgen deprivation therapy (ADT) is the current treatment paradigm in men relapsed with oligometastatic prostate cancer based on the outcome of a phase II randomised controlled study. The immediate (concomitant) use of ADT in this clinical setting potentially augments the efficacy of SBRT by improving systemic disease control. The aim of this study was to compare the clinical outcomes of these two treatment strategies. Materials and methodsEighty-eight patients with up to three oligometastases and controlled primary disease who had been treated using SBRT with immediate or delayed ADT were included in this retrospective analysis. Progression-free survival (PFS), widespread failure-free survival (WFFS) and freedom from further interventions (FFFI) were assessed using Kaplan–Meier and Cox proportional hazard regression methods. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. ResultsThirty-nine patients (44.3%) were treated with SBRT and immediate ADT (continuous ADT, n = 7; intermittent ADT, n = 32) and 49 (55.7%) with SBRT and delayed ADT. The median follow-up was 24 months (interquartile range 13.5–37.0 months). PFS in the immediate and delayed ADT groups were 26 months and 16 months, respectively (P < 0.007). The median WFFS in the immediate ADT group was not reached compared with 21 months in the delayed ADT group (P = 0.025). The 1- and 2-year FFFI in the immediate ADT group were 88% and 64.1%, respectively, significantly higher than those in the delayed ADT group (63.8% and 30.2%, respectively, P < 0.002). Acute toxicities of grade 1–2 occurred in 17.9% of the immediate ADT group and 18.4% of the delayed ADT group (P = 0.96). Only one case of grade 3 late toxicity (pelvic insufficiency) was identified in this study. ConclusionsSBRT with concomitant ADT improves PFS, WFFS and FFFI as compared with SBRT with delayed ADT; this finding needs validation in a prospective, randomised study.

Role of the lysyl oxidase family in organ development (Review).

Lysyl oxidase proteins (LOXs) are amine oxidases, which are mainly located in smooth muscle cells and fibroblasts and serve an important role in the formation of the extracellular matrix (ECM) in a copper-dependent manner. Owing to the ability of LOX proteins to modulate crosslinking between collagens and to promote the deposition of other fibers, they serve crucially in organogenesis and the subsequent organ development, as well as disease initiation and progression. In addition, ECM formation significantly influences organ morphological formation in both cancer- and non-tumor-related diseases, in addition to cellular epigenetic transformation and migration, under the influence of LOXs. A number of different signaling pathways regulate the LOXs expression and their enzymatic activation. The tissue remodeling and transformation process shares some resemblance between oncogenesis and embryogenesis. Additionally the roles that LOXs serve appeared to be stressed during oncogenesis and tumor metastasis. It has also been indicated LOXs have a noteworthy role in non-tumor diseases. Nonetheless, the role of LOXs in systemic or local organ development and disease control remains unknown. In the present study, the essential roles that LOXs play in embryogenesis were unveiled partially, whereas the role of LOXs in organ or systematic development requires further investigations. The present review aimed to discuss the roles of members of the LOX family in the context of the remodeling of organogenesis and organ development. In addition, the consequences of the malfunction of these proteins related to the development of abnormalities and resulting diseases is discussed.

Proton beam radiotherapy for pancreas cancer.

Pancreatic carcinoma is a challenging malignancy to manage with a very poor prognosis. Despite continued difficulties in its management, there have been incremental improvements in outcomes over the past several decades. Achieving the best oncologic outcomes requires a multimodality approach including surgery, chemotherapy, and radiotherapy. Proton radiotherapy enables the delivery of high-dose radiotherapy to the tumor or resection bed while sparing nearby critical organs. Due to their unique physical properties, protons can deliver radiotherapy dose distributions that are not achievable with photons (X-rays) even with advanced photon delivery techniques (e.g., intensity-modulated radiotherapy). Improved dose distributions can lead to reduced treatment toxicity and enable treatment intensification. As better chemotherapy regimens lead to better systemic disease control, it will become increasingly important that local-regional control is achieved. This will in part be accomplished by combining better radiotherapy with more active chemotherapies. Proton radiotherapy provides an excellent means for achieving this.

Effectiveness of a clinic-based randomized controlled intervention for type 2 diabetes management: an innovative model of intensified diabetes management in Mainland China (C-IDM study)

ObjectivesHighly efficient diabetes management programs are needed for tackling diabetes in China. This study aimed to assess the effectiveness of a clinic-based intensified diabetes management model (C-IDM) in Mainland China.Research...

Ocular involvement in systemic lupus erythematosus patients: a paradigm shift based on the experience of a tertiary referral center.

To evaluate ocular involvement in a cohort of systemic lupus erythematosus (SLE) patients of a tertiary referral center and to compare the results with the existing literature. Patients underwent a complete ophthalmological evaluation, including visual acuity, slit-lamp examination, fluorescein staining, Schirmer-I test, Goldmann applanation tonometry, fundoscopy, 10-2 automated threshold visual fields, fundus autofluorescence and spectral-domain optical coherence tomography to screen for hydroxychloroquine (HCQ) macular toxicity. A total of 161 patients (16 men and 145 women) were enrolled in this study. The mean age was 47.6 years and the mean disease duration was 11.5 years. Fifty patients (31.1%) had at least one ocular manifestation of SLE. The most frequent manifestation was dry eye syndrome (12.4%), immediately followed by cataracts (11.2%) and HCQ macular toxicity (11.2%). Among patients with HCQ maculopathy, two presented with an atypical spectral-domain optical coherence tomography pattern. Five patients (3.1%) presented with glaucoma, two patients (1.2%) presented with SLE retinopathy while only one presented with lupus choroidopathy (0.6%). Compared with previous studies, we conclude there has been a significant reduction in disease-related ocular complications, particularly those associated with poor systemic disease control. On the other hand, drug and age-related complications are assuming a prominent role in the ophthalmic care of these patients.