Degree Of Tumor Burden Research Articles

RADT-06. IMPACT OF STATUS OF TUMOR PROGRESSION PRIOR TO STEREOTACTIC RADIOSURGERY ON LOCAL TUMOR CONTROL IN PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY

Abstract INTRODUCTION Prognosis in patients triple-negative breast cancer (TNBC) brain metastases remains poor owing to the lack of treatment targeting pathways. Furthermore, approaches–like surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy–have variable efficacy depending on the degree of tumor burden. The cohort of patients benefit least to targeted therapy and immunotherapy, therefore, forming ideal candidates to evaluate the local tumor control attributed to SRS. This study aimed to characterize intracranial tumor response and clinical outcomes in the patient cohort. PATIENTS and METHODS This retrospective, single-center study included patients with confirmed TNBC brain metastases treated with SRS at the University of Virginia Health. Tumor response, new intracranial tumor development, and survival were investigated. 24 patients with 169 total treated lesions between 2007 and 2021 were assessed. The median age of patients at the initial treatment was 49.1 years. RESULTS One MRI within one month prior to SRS plus the treatment study MRI were evaluated. Tumor progression at the time of SRS led to worse local tumor control following the first SRS treatment (p < 0.0001). 15.1% of total treated lesions demonstrated a complete response, while 48.5% had a partial response. 25.7% of lesions remained stable and 13.5% progressed. Three patients did not have any follow-up imaging to assess initial tumor response due to mortality. For patients with tumor progression, the progression-free survival was 4.93 months. Additionally, new intracranial metastases developed in ten patients over their treatment course. Median overall survival following the first SRS session was 9.83 months (range 0.9 - 37.7 months), with a 1-year and 2-year survival of 54.5% and 22.7%, respectively. CONCLUSION Tumor control in patients with TNBC treated with SRS is unfavorable. Tumor progression prior to SRS might lead to worse tumor control. Further study is warranted to evaluate this phenomenon in a large cohort of patients.

Bridging Therapy in Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Receiving Standard of Care Brexucabtagene Autoleucel: Results from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA)

Introduction: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Bridging therapy, defined as anti-leukemia therapy given between apheresis and lymphodepleting chemotherapy, was permitted on the pivotal ZUMA-3 trial. The optimal bridging therapy is unknown in this setting. Here we report patient and disease characteristics in those receiving bridging therapies prior to brexu-cel and the impact of bridging on clinical outcomes in a large multicenter cohort. Methods and Results: ROCCA includes 25 US institutions contributing retrospective data from 152 B-ALL patients treated with standard of care brexu-cel between 2021-2023. Ninety-nine patients (65%) received bridging therapy, while 53 patients (35%) received no bridging therapy. Bridging therapy consisted of cytotoxic chemotherapy ( n=65, 66%), immunotherapy ( n=26, 26%; 23 inotuzumab, 3 blinatumomab), tyrosine kinase inhibitors (TKI) ( n=20, 20%; 16 ponatinib), steroids only ( n=10, 10%), and intrathecal chemotherapy ( n=22, 22%). The median age of the cohort was 46 (IQR 32-61). Patients were heavily pre-treated with a median of 4 prior lines of therapy. The median days from apheresis to infusion was 33 (IQR 26-42). 119 patients had known pre-apheresis blast counts; the bridging group had higher pre-apheresis blast burden, with 21 of 76 patients (28%) having ≥ 50% blasts compared to only 5 of 43 patients (12%) in the no bridging group ( p=0.02). In addition, more patients who received bridging had pre-apheresis extramedullary disease (32% vs. 15%, p=0.02). All other baseline characteristics were similar between the two groups (Table 1). Fifty-four (54%) patients had response assessment after bridging therapy and prior to brexu-cel infusion. In patients who received inotuzumab for pre-apheresis active disease, defined as ≥ 5% blasts, 6 of 13 (46%) who had post-bridging assessment achieved a complete response (CR; 5 measurable residual disease (MRD)+, 1 MRD-), with a mean proportional reduction in blast burden of 46% from baseline. In contrast, after chemotherapy bridging, only 2 of 16 patients (13%) with pre-apheresis active disease had a CR. Patients receiving chemotherapy bridging had a mean proportional increase in blast burden of 4.4%. In recipients of TKI bridging, 2 of 4 patients (50%) with pre-apheresis active disease had a CR. Compared to no bridging, patients in the bridging group had similar rates of grade 3 or 4 CRS (9% bridging vs. 8% no bridging, p=0.73) and grade 3 or 4 ICANS (34% vs. 26%, p=0.32). In univariate analysis, there was no statistically significant difference in day 28 response with 63 patients (72%) achieving MRD- complete response in the bridging group as compared to 36 patients (78%) in the no bridging group ( p=0.60). Non-relapse mortality was similar between the two groups (17% bridging vs. 9% no bridging, p=0.20). Overall survival (OS) and progression-free survival (PFS) were superior in the no bridging group: 1-year OS 74.7% vs 56.8% (log-rank p=0.04), and 1-year PFS 57.3% vs 41.7% (log-rank p=0.04). In a multivariate analysis stratified by bridging and pre-apheresis disease burden, patients with pre-apheresis blasts ≥ 5% and bridging had worse survival than ≥ 5% blasts and no bridging: 1-year OS 45.3% vs. 87.5% and 1-year PFS 27.7% vs. 64.3% (Figure 1). However, patients with < 5% blasts had similar survival regardless of bridging. Conclusions: In our real-world analysis, adults with R/R B-ALL receiving bridging therapy had a higher disease burden at baseline. Despite greater baseline disease, there were no significant differences in toxicity and day 28 response in those receiving bridging therapy vs. not. While survival was inferior in patients with pre-apheresis active disease who received bridging, this may be confounded by the degree of tumor burden. In patients with < 5% blasts pre-apheresis, bridging did not impact survival. Furthermore, inotuzumab bridging demonstrated the most significant disease debulking. However, the comparisons in this study are limited by the variability in practice for post-bridging disease reassessment and the small proportion of patients with active disease who did not receive bridging. A more uniform approach to peri-CAR disease assessment would enable more robust study of optimal bridging strategies.

SAT059 Metastatic Insulinoma Diagnosed Postpartum

Abstract Disclosure: A. Faber: None. H. Lam: None. R. Simon: None. Introduction: Insulinomas are rare neuroendocrine tumors derived from the beta cells of the pancreas. These tumors generally occur at a rate of four cases per million per year, and they are seen across all demographics. Affected patients present with symptoms of hypoglycemia, including confusion, diaphoresis, and palpitations. Insulinomas occur as single or multiple tumors, and can be benign or malignant. Insulinomas with metastases are defined as malignant. The primary treatment is surgical resection. However, in the case of metastatic insulinomas prognosis can be quite poor with limited treatment options. Case Presentation: A 24-year-old female employed as a nurse with otherwise negative medical history originally presented around 3 months postpartum with epigastric pain which was attributed to gas. Symptoms progressed to include lightheadedness, palpitations, and sweating. She checked her blood glucose during these events and noted it to be consistently in the 30s-40s. She would treat these episodes with food and had short-term improvement in symptoms. She presented to an outside hospital where imaging revealed: hepatomegaly with innumerable hypodense liver lesions, hypo-enhancing pancreatic head lesion, sclerotic focus in T4 vertebral body, as well as multiple enlarged upper abdominal lymph nodes including peripancreatic, porta hepatis, and gastrohepatic. Liver biopsy revealed well-differentiated neuroendocrine tumor, WHO grade 3 likely from a pancreatic primary and chemotherapy was initiated with carboplatin and paclitaxel with some response. However, hypoglycemia became refractory to management with 5% dextrose drip, so she was transferred to our facility for escalation of care. TPN was initiated and dextrose drip was escalated eventually to 40% dextrose. She was also given octreotide, hydrocortisone, and eventually diazoxide. Given degree of tumor burden as well as abdominal ascites and clinical condition, surgery was deemed high risk and not recommended. Tumor board meeting was held and her chemotherapy regimen was changed to Carboplatin/Etoposide/Atezolizumab. She subsequently underwent hepatic artery embolization twice with improvement of hypoglycemia. Despite decreasing dextrose drip requirements by over 50%, patient was unable to be liberated from dextrose infusion and had multiple discussions about management options and prognosis. The patient eventually elected to go home with home hospice. Discussion: Insulinoma diagnosed in pregnancy or shortly after pregnancy is extremely rare. There are only three case reports of malignant insulinoma diagnosed in or after pregnancy. Given the degree of extensive metastases at time of presentation, we expect our patient’s insulinoma was present prior to delivery. Hypoglycemia may have only manifested in the postpartum period when there was decreased levels of placenta-derived counterregulatory hormones. Presentation: Saturday, June 17, 2023

A Review of the Use of Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignancy in Pediatric Patients.

Hyperthermic intraperitoneal chemotherapy (HIPEC) can directly target microscopic peritoneal disease, has achieved regular consideration in the treatment of several adult cancer types, and is more recently being studied in pediatrics. This review paper provides an overview of the use of this modality in pediatrics in order to identify medication choice, discuss post-operative morbidity and mortality, and evaluate impact on overall survival. Four databases were searched including Scopus, PubMed, Embase, and CINAHL and ultimately 37 papers documenting the use of this modality comprising 264 pediatric patients were included. Malignancies treated include desmoplastic small round cell tumor, rhabdomyosarcoma, angiosarcoma, colorectal carcinoma, and mesothelioma, with several rarer tumor types. Cisplatin was the most commonly used drug for HIPEC at varying concentrations for 30-90 min in duration at temperatures of approximately 41-42 °C. Reported toxicities were generally self-limited and there was no post-operative mortality. The impact on overall survival versus systemic chemotherapy and debulking surgery is uncertain due to lack of clinical trials and very small sample size across tumor subsets and the overall pediatric population. The relationship between degree of tumor burden and extent of surgical debulking needs to be further clarified. Future directions include prospective clinical trials, establishment of patient databases to facilitate standardization of HIPEC in pediatric patients, and additional approaches to optimize HIPEC.

Deep Immune Profiling in Multiple Myeloma at Diagnosis and Under Lenalidomide Maintenance Therapy

IntroductionHere we report the results of one of the secondary endpoints of the Finnish Myeloma Group-MM02 study; composition of bone marrow (BM) immune cell subsets at treatment start and during lenalidomide (Len) maintenance focusing on 2 different response groups: good responders (GRs) and poor responders (PRs) at pre- and post-treatment stages. We evaluated the BM immune profile with CyTOF (cytometry by time-of-flight). Our hypothesis was that there would be distinct differences in immune cell profiles between patients with good and poor response, especially in the T and NK cell subsets.Patients and methodsTwenty-two patients were included in this CyTOF study. Eighteen were NDMM patients from FMG-MM02 study who received 3 RVD cycles followed by ASCT. Len started 3 months after ASCT 10 mg/day in 21/28-day cycles until progression or toxicity. BM samples were collected to the Finnish Hematology Registry Clinical Biobank (FHRB Biobank) at several timepoints; from 18 patients at diagnosis, from 11 patients 1 st sample at good response during Len and 2 nd sample if this good response was maintained and from 5 patients at relapse during Len. The patients in the good response cohort (n=11) had progression-free survival (PFS) > 5 years. For comparison, we included 4 BM samples from the FHRB Biobank, taken at a good response after ASCT from MM patients without exposure to Len.ResultsWith a median follow-up of 81 months (13-97) the median PFS was not reached in the good response (GR) cohort and was 18 months in the poor response (PR) cohort. The 1 st GR samples were collected after a median of 21 (6-46) months of Len. The 2 nd samples in GR cohort were collected after a median of 56 (45-67) months of Len. The PR samples were taken after a median of 6 (2-23) months of Len.CyTOF analysis revealed distinct good and poor responder's immune signatures at baseline level. GR, baseline group has shifted phenotype of T cells toward the CD8 T cells, expressing markers, attributed to the cytotoxicity (CD45RA, CD57), as well as having slightly higher abundance of CD8 TE and lower abundance of CD8 naïve T cells. Total T cells amounts were significantly higher in GR. Increased expression of CD56, CD57, and CD16 were also seen on NK cells in GR at the baseline, indicating both maturation and cytotoxic potential of NKs. In contrast, a significant decrease of CD56 and CD16 expression suggesting reduced cytotoxic potential and increase of CD57 were seen on NKs in PR, baseline indicating senescence status a phenotype associated with exhaustion.By using viSNE we discovered two novel populations - MAC1, and MAC2, - associated with disease pathogenesis. We further investigated the composition of these populations, and it appears that MAC1 expressed CD38+CD56+CD45-CD19- presumably malignant plasma cells and MAC2 expressed CD45- CD14+CD38+CD56+TCRgd+CCR7+CCR6+CXCR4+ CXCR3+CXCR5+CD294+, which might be the novel populations, having the features of myeloid suppressor cells. These two immune cells were higher in PR (9.2% and 8.2%, respectively) at baseline as compared to the GR (2.3% and 1.7%).NKs, T cells, and B cells showed a high expression of monocytic marker CD14 and chemokine receptors (CCR7, CCR6, CXCR4, CXCR3, and CXCR5) in PR both at baseline and relapse. This might be attributed to either biological features of MM environment, or the high level of interaction between these populations and monocytes, which left traces of their membranes on the non-monocytic populations.ConclusionsPatients, responded to the treatment, have higher abundances of effector/cytotoxic cells, expressing higher levels of CD57 and/or CD45RA for T cells, and CD57, CD16, and CD56 for NK cells indicating proper differentiation and maturation of T, and NK cells to effector and cytotoxic subsets. Additionally, those patients have less degree of tumor burden as well as decreased expression of chemokine receptors. During the therapy administration, good responders show the increase in effector memory CD4 and CD8 subsets of T cells abundance, indicating even the higher cytotoxic effect of immune system. DisclosuresSilvennoinen: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Luoma: Amgen: Honoraria; Janssen: Honoraria; Incyte: Honoraria. Anttila: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Säily: Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Partanen: Takeda: Honoraria; Abbvie: Honoraria; Behring: Honoraria. Heckman: Novartis: Research Funding; Orion Pharma: Research Funding; Celgene/BMS: Research Funding; Oncopeptides: Consultancy, Research Funding; Kronos Bio, Inc.: Research Funding.

P-067: High dimensional CyTOF analysis of the immune system of multiple myeloma patients with different responses to lenalidomide maintenance

<h3>Background</h3> In this phase 2 study patients received 3 cycles of RVD (lenalidomide, bortezomib and dexamethasone) followed by autologous stem cell transplantation (ASCT) and lenalidomide maintenance. We evaluated the bone marrow (BM) immune profile with CyTOF (cytometry by time-of-flight) at treatment start and during lenalidomide maintenance focusing on two different response groups: good and poor responders at pre- and post-treatment phases. Our hypothesis was that there could be distinct differences in immune cell profiles between these groups, especially in T and NK cell subsets and exhausted T-cells. <h3>Methods</h3> Twenty-six patients were included in this study, 18 from this trial. BM samples were collected from all 18 patients at diagnosis, from 11 the 1st sample when achieved good response during maintenance after a median of 21 (6-46) months and the 2nd sample if good response was maintained after a median of 56 (45-67) months and from 5 patients at relapse after a median of 6 (2-23) months. Patients in good response cohort (n=11) had progression-free survival (PFS) > 5 years. For comparison we included 4 BM samples, taken at good response after ASCT from MM patients not exposed to lenalidomide and 4 BM samples collected from age-matched, healthy donors. <h3>Results</h3> With a median follow-up of 81 (13-97) months the median PFS was not reached in the good response cohort and was less than 18 months in the poor response cohort. CyTOF analysis revealed distinct good (GR) and poor responder's (PR) immune signatures at baseline level. GR, baseline group has shifted phenotype of T cells toward the CD8 T cells, expressing markers, attributed to the cytotoxicity (CD45RA, CD57), as well as having slightly higher abundance of CD8 TE and lower abundance of CD8 naive T cells. Total T cell amounts were significantly higher in good responders. Increased expression of CD56, CD57, and CD16 were also seen on NK cells in good responders at the baseline, indicating both maturation and cytotoxic potential of NKs. In contrast, a significant decrease of CD56 and CD16 expression suggesting reduced cytotoxic potential and increase of CD57 were seen on NKs in poor responders, baseline indicating senescence status a phenotype associated with exhaustion. Treatment stimulates the expression of cytotoxic/effector-like phenotype on T cells which is confirmed by the significantly increased amounts of CD4 and CD8 effector memory cells, with the respective decrease of naive cells. <h3>Conclusions</h3> Patients responded to the treatment, have higher effector/cytotoxic cells, expressing higher levels of CD57 and/or CD45RA for T cells, and CD57, CD16, and CD56 for NK cells. Additionally, those patients have less degree of tumor burden as well as decreased expression of chemokine receptors (CCR7, CCR6, CXCR4, CXCR3, and CXCR5). Good responders showed the increase in effector memory CD4 and CD8 subsets of T cells abundance, indicating even the higher cytotoxic effect of immune system.

What Should Be the Rules for Downstaging for Hepatocellular Carcinoma?

Liver transplantation remains the main curative treatment method for hepatocellular carcinoma. There are several criteria for hepatocellular carcinoma to be eligible for liver transplantation, and it depends on main transplantation centers worldwide. Locoregional treatments and downstaging protocols are used for either to achieve these criteria or to prevent drop outs on the transplant waiting lists. But who can benefit from these bridging therapies effectively for the main purpose of curative treatment? Main contraindications are known for locoregional treatments like cirrhosis or low hepatic function, total main portal vein occlusion, and extrahepatic metastasis. HCCs, which are confined to liver but have high tumor burden, remains the main controversial issue. On this aspect, we reviewed the literature for downstaging protocols for hepatocellular carcinoma with their effect on survival and recurrence rates after liver transplantation. Although candidates for downstaging is still controversial, with the absence of main contraindications, LRT can be applied to selected HCCs, which have a certain degree of tumor burden.

Interventional Liver-Directed Therapy for Neuroendocrine Metastases: Current Status and Future Directions.

Liver-directed therapy should be considered for patients with unresectable liver metastases from neuroendocrine tumor if symptomatic or progressing despite medical management. Our experience and current literature shows that the bland embolization, chemoembolization, and radioembolization are very effective in controlling symptoms and disease burden in the liver, and that these embolization modalities are similar in terms of efficacy and radiologic response. Their safety profiles differ, however, with recent studies suggesting an increase in biliary toxicity with drug-eluting bead chemoembolization over conventional chemoembolization, and a risk of long-term hepatotoxicity with radioembolization. For this reason, we tailor the type of embolotherapy to each patient according to their clinical status, symptoms, degree of tumor burden, histologic grade, and life expectancy. We do not recommend a "one-size-fits-all" approach. Our general strategy is to use bland embolization as first-line embolotherapy, and radioembolization for patients with high-grade tumors or who have failed other embolotherapy.

EUS-Guided Portal Venous Sampling of Circulating Tumor Cells.

Although liquid biopsies hold significant promise in the management of patients with cancer, peripheral blood analyses remain dependent on the degree of tumor burden with prohibitively low yields until the cancer is widely metastatic. Multiple lines of evidence support a dynamic, spatiotemporal localization of circulating tumor cells (CTCs) supporting specific targeting of vascular compartments, such as the portal vein. This review discusses the literature evaluating the possibility of portal venous blood as a new, potentially higher yield liquid biopsy and the current devices and techniques for endoscopic ultrasound (EUS)-guided portal venous sampling for CTC detection. Two recent studies in pancreatic cancer have demonstrated that portal venous blood can be safely sampled via EUS and consistently yields significantly higher CTC counts compared with matched peripheral blood. EUS-acquired samples can be used for molecular testing, clinical prognostication, and drug sensitivity analyses. Portal venous CTCs are identified in higher quantity relative to peripheral blood and can be safely obtained via EUS. Further studies are required to demonstrate the clinical utility of EUS-guided portal venous tumor material enrichment and analysis; however, obtaining EUS-guided "liquid biopsies" appears to merit significant consideration for procedural adoption.

3138 Unusual Gastrointestinal Petechial Bleeding of the Small Bowel Associated With Newly Diagnosed Chronic Myeloid Leukemia

INTRODUCTION: Chronic myeloid leukemia (CML) often is diagnosed in the chronic phase based off routine laboratory analysis in asymptomatic patients with findings include splenomegaly, anemia, leukocytosis, and thrombocytosis. Patients less commonly present with bleeding due to platelet dysfunction. In the case presented, a patient presented with unusual petechial bleeding of the small bowel found on video capsule endoscopy (VCE) as the initial symptom of undiagnosed CML which is highly atypical. CASE DESCRIPTION/METHODS: A 79-year-old Caucasian male with a past medical history significant for atrial flutter status-post ablation (not on anti-coagulation) presented to the emergency room with maroon colored stools for 2 days with no other complaints. He denied abdominal pain, nausea, vomiting, or weight loss. Physical exam was benign with vital signs within normal limits. Laboratory analysis revealed white blood cell count of 84.9 t/cmm with 89.9% segmented neutrophils and hemoglobin (HGB) of 10.2 g/dL (previous HGB 14.4 g/dL). The patient was admitted for gastrointestinal (GI) bleeding and malignancy work up. HGB down trended to 7.7 g/dL and an esophagogastroduodenoscopy (EGD) was performed showing no abnormalities. Due to the continued drop in HGB, a colonoscopy was performed which showed old blood in the colon with no identifiable source of bleeding. VCE, interestingly, showed multiple clustered pinpoint petechiae in the ileum. Concurrently, it was suspected that the patient had underlying CML given absence of infection and findings of 1% blasts, basophilia, and eosinophilia. Bone marrow biopsy showed hypercellular bone with myeloid hyperplasia with FISH positive for BCR/ABL confirming CML. It was unknown if the VCE findings may have been related to the patient's newly diagnosed CML. DISCUSSION: Anemia is observed in about a third of the patients with newly diagnosed CML depending on the degree of tumor burden. Due to platelet dysfunction, patients may present with bleeding. Because of the significant HGB drop and melena, GI bleeding work up was initiated and ultimately identified a highly unusual source of bleeding. The VCE yielded unexpected images of petechial hemorrhage within the small bowel which was most likely secondary to the underlying malignancy. The case highlights the importance of ruling out sources of GI bleeding in the setting of severe anemia rather than anchoring on the diagnosis of CML. To our knowledge, these VCE findings have not been documented in CML.

Liquid biopsies in pancreatic cancer: targeting the portal vein

Abstract Pancreatic cancer is a highly lethal malignancy with poor overall survival due to silent progression until primary tumor growth or metastatic dissemination develops clinical symptoms. Even in the minority of patients with early diagnosis and candidacy for curative intent surgery, postoperative recurrence after surgical resection is very frequent. Due to these findings, efforts to identify minimally invasive ways to provide earlier diagnosis and enhanced prognostication are increasingly warranted. Liquid biopsies assessing for tumor derived materials shed into the blood are a promising tool to accomplish this goal; however, in pancreatic cancer, peripheral blood analyses remain dependent on the degree of tumor burden with a prohibitively low yield until the cancer is widely metastatic. To overcome this limitation, increasing literature has emerged evaluating the possibility of portal venous blood as a new, potentially higher yield liquid biopsy target in pancreatic cancer. This review will discuss the current literature and clinical application potential of mesenteric vasculature, or portal venous blood, as liquid biopsies in the diagnosis, prognosis and management of patients with pancreatic cancer.

Abstract 384: Detection of circulating melanoma cells in paired arterial and venous specimens from uveal melanoma patients with hepatic metastatic

Abstract Background: Circulating tumor cells (CTCs) represent a surrogate biomarker for hematogenous metastases. The detection of CTCs has gained increasing interest for prediction of clinical outcome. However, it remains to be determined whether uveal melanoma cells circulating in a peripheral vein predict systemic recurrence and poorer overall prognosis. Uveal melanoma, the most common primary cancer of the eye in adults, is unique in that the uveal tract is devoid of lymphatics. Since systemic recurrence develops exclusively via hematogenous spread, patients with uveal melanomas present a special opportunity to explore the prognostic potential of CTCs. Although the lung is the first organ through which venous drainage from the affected eye passes and indeed the only organ through which all venous blood must pass, 80-95% of systemic metastases are found first in the liver without development of lung metastases. To address these issues, we investigated the numbers of CTCs in paired arterial (femoral) and venous (antecubital) blood specimens obtained from uveal melanoma patients with hepatic metastases. Methods: CTCs in blood specimens were measured in 17 uveal melanoma patients with multiple hepatic metastases, including 10 patients with liver-only metastases and 7 patients with hepatic and extra-hepatic metastases. Peripheral arterial and venous blood specimens were collected at the same time prior to liver directed treatment. CTCs were analyzed using CellTracks Circulating melanoma Cell Kit by CellSearch System. The clinical information and sources of blood specimens were blinded when CTCs were analyzed. Result: CTCs were detectable from all 17 arterial blood specimens (100%) (median 5, range 1 to 168). In contrast, much smaller numbers of CTCs were detectable in 52.9% (9/17) of venous blood specimens (median 1, range 0 to 8) from the same patients. In terms of degree of tumor burden, patients who have hepatic as well as extra-hepatic metastasis showed higher numbers of arterial CTCs (median 12, range 5 to 168), compared to patients who have liver-only metastasis (median 4, range 1 to 11). More importantly, there is no significant correlation between numbers of arterial CTCs and the degree of tumor volume in the liver in patients who have liver-only metastases. Conclusions: Using this technology, the detection of uveal melanoma cells in peripheral blood is feasible. Peripheral capillary beds effectively filter CTCs from venous blood; thus venous blood might not be the best source for measurement of CTCs in patients with metastatic uveal melanoma. The paucity of clinically evident non-hepatic metastases despite the effective filtration by peripheral capillary beds remains unexplained and may be a demonstration of the “seed and soil” hypothesis. CTCs are a non-invasive source of uveal melanoma cells for evaluating tumor biology. Further investigation is warranted. Citation Format: Mizue Terai, Zhaomei Mu, David Eschelman, Carin Gonsalves, Ken Kageyama, Michael J. Mastrangelo, Marlana Orloff, Ryan Weight, Massimo Cristofanilli, Takami Sato. Detection of circulating melanoma cells in paired arterial and venous specimens from uveal melanoma patients with hepatic metastatic. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 384. doi:10.1158/1538-7445.AM2015-384

Are all chimeric antigen receptors created equal?

In the report accompanying this article, Kochenderfer et al discuss the efficacy of autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) in patients with relapsed diffuse large B-cell lymphoma. Although previous reports have demonstrated significant antitumor activity in low-grade B-cell malignancies and B-cell acute lymphoblastic leukemia (ALL), this is the first report to our knowledge to demonstrate the efficacy of CD19-targeted CAR T cells in patients with diffuse large B-cell lymphoma. A CAR is a recombinant receptor constructs composed of an extracellular single-chain variable fragment (scFv) derived from an antibody, linked to a transmembrane domain, which is further linked to one or more intracellular T-cell signaling domains (Fig 1). Because CARs combine the binding domain of an antibody and T-cell signaling moieties, they can redirect T-cell specificity to the tumor in an HLA-independent fashion and activate the CAR-modified T lymphocytes to lyse targeted tumor cells. Initial first-generation CARs were constructed through the fusion of an scFv-based antigen binding domain to an inert CD8 transmembrane domain, linked to a cytoplasmic signaling domain derived from the CD3or Fc receptor chains (Fig 1). Although T cells expressing first-generation CARs effectively engaged the target antigens, limited T-cell proliferation and diminished cytolytic activities were observed because of the lack of T-cell costimulation. For optimal activation and proliferation, T cells require both T-cell receptor engagement and signaling (termed signal 1), as well as costimulatory signaling through costimulatory receptors (ie, CD28, 4-1BB, OX-40) on T cells binding to cognate ligands (ie, CD80/86, 4-1BBL, OX-40L) expressed either by the targeted tumor cell or professional antigen-presenting cells (termed signal 2). To overcome the lack of T-cell costimulation (signal 2), firstgeneration CARs were further modified by incorporating the cytoplasmic signaling domains of T-cell costimulatory receptors. These second-generation CARs (Fig 1) enhanced signaling strength and persistence of the modified T cells, leading to superior antitumor activity. However, it remains unclear whether any particular second-generation CAR design is superior to the other. In one study by Carpenito et al, both CD28and 4-1BB–based CAR-modified T cells had the same antitumor activity, but the 4-1BB–based CAR enhanced in vivo persistence of T cells. In contrast, another study failed to demonstrate any significant difference between CD28and 4-1BB–based second-generation CARs with regard to proliferation, potency, antitumor efficacy, and persistence of the T cells. More recently, third-generation CARs containing tandem cytoplasmic signaling domains from two costimulatory receptors (Fig 1) were tested in certain mouse models, but clinical experience so far has been limited. Initial clinical results with first-generation CD19-targeted CAR-modified T cells were disappointing, but second-generation CAR-modified T cells displayed significantly enhanced expansion and persistence in patients with B-cell lymphoma. Using either CD28or 4-1BB–based second-generation CD19-specific CARs, investigators at Memorial Sloan Kettering Cancer Center (MSKCC), the University of Pennsylvania, and the National Cancer Institute published initial promising results of phase I clinical trials, reporting durable antitumor efficacy in patients with indolent B-cell malignancies, including chronic lymphocytic leukemia (CLL), and more recently reporting dramatic clinical responses in patients with relapsed B-cell ALL. These trials varied significantly with respect to infused T-cell product; CAR design, including scFv and costimulatory domains (CD28 v 4-1BB); means of gene transfer (retrovirus v lentivirus); ex vivo T-cell expansion; T-cell dose; intensity of conditioning chemotherapy; degree of tumor burden at the time of therapy; and age of the treated patient population. All of these variables make it difficult to compare results from one trial with those of another and the efficacy of one CAR T cell with that of another. Hinge First-generation CAR Second-generation CAR Third-generation CAR

Rapid clearance of rituximab may contribute to the continued high incidence of autoimmune hematologic complications of chemoimmunotherapy for chronic lymphocytic leukemia

Rituximab is an effective treatment for autoimmune cytopenias associated with chronic lymphocytic leukemia. Despite the incorporation of rituximab into fludarabine-based chemotherapy regimens, the incidence of autoimmune cytopenias has remained high. Inadequate rituximab exposure due to rapid antibody clearance may be a contributing factor. To test this hypothesis, we measured serum rituximab levels in patients treated with fludarabine and rituximab (375 mg/m(2)). All patients had undetectable rituximab trough levels by the end of cycle 1, and one-third had undetectable levels already on Day 6 of cycle 1. Although rituximab trough levels increased progressively with each cycle, only by cycle 4 did the median trough level exceed 10 ug/mL. The median half-life of rituximab during cycle 1 was 27 hours, compared to 199 hours during cycle 4 (P<0.0001). There was a significant inverse correlation between the rituximab half-life in cycle 1 and the degree of tumor burden (P=0.02). Two patients who were identified as having subclinical autoimmune hemolysis prior to therapy were given additional doses of rituximab during the initial cycles of therapy and did not develop clinically significant hemolysis. One patient who developed clinically significant hemolysis during therapy was given additional rituximab doses during cycles 3-5 and was able to successfully complete his treatment. In conclusion, rituximab is cleared so rapidly during the initial cycles of therapy for chronic lymphocytic leukemia that most patients have only transient serum levels. More frequent dosing of rituximab may be required to prevent autoimmune complications in at-risk patients (clinicaltrials.gov identifier:00001586).

Difference in global hepatic enhancement assessed by dynamic CT in normal subjects and patients with hepatic metastases.

Our goal was to determine if there are differences in liver densitometry parameters using helical CT between normal subjects and subjects with liver metastases. One-hundred fifty subjects (64 with normal livers and 86 with CT-visible hepatic metastases) underwent dual phase helical scanning of the liver. Images were obtained in the "arterial" (early) and "venous" (late) phases of hepatic enhancement. Densitometry measurements were obtained from the liver (distinct from obvious lesions or vessels) and aorta at 25, 40, 75, and 90 s. Enhancement values at the same time points were calculated in 73 subjects in whom noncontrast images of the liver were available. A peak liver densitometry value was also determined. Several ratios were determined for each time point: the liver/aortic ratio (L/A), liver/liver peak ratio (L/P), liver enhancement/aortic enhancement ratio (LE/AE), and liver enhancement/liver peak enhancement ratio (LE/LPE). The degree of tumor burden in the hepatic metastatic group was assessed in each case. Values for L/A, L/P, LE/AE, and LE/LPE at 25 and 40 s were significantly (p < 0.05) higher in the liver metastases group than the normal liver group. Enhancement ratios were even more elevated in breast cancer, which can have hypervascular metastases. These CT parameters did not show significant differences when analyzed according to the degree of hepatic metastatic tumor burden. All densitometry parameters and ratios obtained at 75 and 90 s were not significantly different between the two groups. In the early phase of bolus intravenous contrast agent administration, the visually normal portion of the liver parenchyma in patients with hepatic metastases enhances to a greater degree than the liver in normal subjects. This may reflect generalized increased hepatic arterial flow in tumor-bearing livers and has the potential to increase the sensitivity of CT for detection of hepatic metastases.

Hyaline Droplet Accumulation in Rodent Kidney Proximal Tubules: An Association with Histiocytic Sarcoma

Since recognition during the last decade that certain renal carcinogens can initially cause an accumulation of hyaline (protein) droplets in proximal tubules of male rats, it has become appropriate to establish whether this phenomenon of protein overload can also occur in rodent kidneys unrelated to chemical treatment. Kidney tissue from a number of selected rodent studies held in the National Toxicology Program (NTP) or Food and Drug Administration (FDA) archives were evaluated for hyaline droplet accumulation in proximal tubules. The survey concentrated on rats and mice of both sexes bearing hematopoietic tumors, as our preliminary observations had suggested this direction of study. The tissues of 101 Sprague-Dawley, 25 Osborne-Mendel, and 70 Fischer 344 rats and 96 B6C3F1 mice were examined. These animals provided an assortment of tumors including histiocytic sarcoma, lymphocytic lymphoma, mononuclear cell leukemia, and sarcoma. Hyaline droplet accumulation, primarily involving the P2 segment of proximal tubules, was diagnosed in 96% of rats with histiocytic sarcoma (74/77 cases in Sprague-Dawley, 17/18 in Osborne-Mendels, 7/7 in Fischers) and in 55% of B6C3F1 mice with histiocytic sarcoma (18/33 cases). There appeared to be a qualitative correlation between hyaline droplet accumulation and degree of tumor burden. Thus, in cases negative for hyaline droplets, the tumor was often confined to a single location, while increasing involvement of proximal segments beyond P2 occurred with more extensive multi-organ dissemination of the tumor. By immunohistochemistry on 11 cases of rat and 8 cases of mouse histiocytic sarcoma, the protein in hyaline droplets was identified as lysozyme, a known major secretory product of monocytes and macrophages. The hyaline droplets were negative for alpha 1-antitrypsin, alpha 2u-globulin, rat or mouse immunoglobulin, and albumin. More sparsely scattered droplets and granules present in proximal tubules of Fischer rats with mononuclear cell leukemia were negative for lysozyme but positive for either iron or lipofuscin pigment. The study establishes a clear association between renal tubule hyaline droplet and lysozyme accumulation in rats and mice with histiocytic sarcoma. Hyaline droplets secondary to neoplasia should be distinguished from chemically-induced hyaline droplet nephropathy in the male rat involving alpha 2u-globulin.

Dissemination of disease following transurethral resection for locally advanced prostate cancer

Between 1974 and 1978, 258 patients with clinical Stage C adenocarcinoma of the prostate were treated at the U. T. M.D. Anderson Hospital in Houston. Of these, 208 were considered evaluable for a review of the impact of transurethral resection (TUR) on the dissemination of disease. After TUR, the incidence of disease progression was 38.9 per cent, compared with 36.4 per cent for patients who did not undergo TUR. There were significant differences in both incidence of progression (31.2 % versus 55.6 %, p = 0.002) and time to progression (p < 0.001) when patients were divided into Stages C1 and C2 (presence or absence of pelvic side wall fixation) irrespective of their TUR status. Therefore, it appears that for patients with locally advanced prostate cancer, the degree of tumor burden and not the TUR status has a significant influence on disease progression.

Hepatic arterial infusion with floxuridine and cisplatin: overriding importance of antitumor effect versus degree of tumor burden as determinants of survival among patients with colorectal cancer.

Cisplatin (CDDP) was combined with floxuridine (FUDR) and delivered into the hepatic arteries of 29 patients as induction therapy for colorectal cancer metastatic to the liver. Mitomycin C and FUDR combination was substituted after progression or when response had peaked. Chemotherapy was delivered with an Infusaid pump (Infusaid Corp; Norwood, Mass; 14 patients), Medtronic programmable drug administration device (Medtronic, Inc, Minneapolis; two patients), or percutaneously placed catheters (13 patients). Complete disappearance of liver metastases was observed in four patients and 11 additional patients had a partial remission as determined by computed tomography (CT) scan and substantiated at times by angiography, for a total response rate of 52%. Response as determined by imaging techniques coincided with a concurrent decrease in carcinoembryonic antigen (CEA) and improvement in performance status. The severity of tumor burden was correlated with the response to therapy and survival. Among those patients who responded to arterial chemotherapy, differences in disease severity did not significantly influence survival. Median survival among responders with greater than 25% liver replacement by tumor was 14 months (P = .28), compared with 28 months for those patients with less than 25% liver replacement. In contrast, differences in tumor burden significantly affected survival among patients who failed to respond to chemotherapy; median survival among nonresponding patients with greater than 25% liver replacement was 4 months, compared with 8 months for those who had less than 25% liver replacement (P = .01). The presence of minimal extrahepatic disease at the time of initiation of intraarterial treatment did not seem to have a significant detrimental effect on survival. The study suggests that hepatic tumor response to arterial administration of CDDP and FUDR and mitomycin C and FUDR is clinically significant because it overrides the effect of tumor burden on survival among patients who have colorectal cancer with liver metastases and may offer effective palliation.

Indirect Leukocyte Migration Inhibition Reactions to a 3-&lt;italic&gt;M&lt;/italic&gt; KCI Extract of Lung Adenocarcinoma by Lung Cancer Patients&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;

Mononuclear (MN) cells from the peripheral blood of lung cancer patients were tested for their ability to respond to a 3-M KCl extract of adenocarcinoma of lung with the use of an indirect leukocyte migration inhibition (LMl) assay. Antigen-stimulated MN cell cultures were evaluated for leukocyte inhibitory factor production by their ability to inhibit the migration of indicator polymorphonuclear cells from agarose droplets. When supernatants were prepared in conventional round-bottomed tubes (5X10(6) cell/tube), 25 of 44 (57%) lung cancer patients had positive indirect LMl responses to the 7661 antigen as compared to only 2 of the 30 (7%) normal donors. When supernatants were prepared in conical microtubes, with 10 times fewer MN cells, similar results were obtained. Patients with all histologic types of lung cancer had a similar incidence of reactivity, and reactivity of untreated patients did not appear to be related to stage of disease or degree of tumor burden. Surgical removal of the tumor appeared to decrease the incidence of reactivity in the 1- to 12-month postoperative period. These results strongly suggest that the LMl reactivity against lung tumor extracts is lymphokine mediated, inducing cellular responses by the patients against such antigens.