Large Tumor Burden Research Articles

Association Between BRCA Status and Triple-Negative Breast Cancer: A Meta-Analysis.

Triple-negative breast cancer (TNBC) is a subtype of aggressive breast cancer and characterized by a lack of the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. BRCA genes are tumor-suppressor genes that are involved in DNA damage repair and mutations of BRCA genes may increase the risk of developing breast cancer and/or ovarian cancer due to defective DNA repair mechanisms. However, the relationship between BRCA status and TNBC needs to be further investigated and validated. The aim of this meta-analysis was to evaluate the association between BRCA status and TNBC. We systematically searched the electronic databases of MEDLINE (PubMed), Embase, and Cochrane Library to identify relevant publications from April, 1959 to November, 2017. The data from the studies were examined by a meta-analysis using STATA software to calculate the odds ratio (OR) with 95% confidence interval (CI) by fixed-effect and random-effect models. We identified 16 qualified studies from 527 publications with 46,870 breast cancer patients including 868 BRCA1 mutations (BRCA1Mut) carriers, 739 BRCA2 mutations (BRCA2Mut) carriers, and 45,263 non-carriers. The results showed that breast cancer patients with BRCA1Mut carriers were more likely to have TNBC than those of BRCA2Mut carriers (OR: 3.292; 95% CI: 2.773–3.909) or non-carriers (OR: 8.889; 95% CI: 6.925–11.410). Furthermore, high expression of nuclear grade and large tumor burden (>2 cm) were significantly more common in breast cancer patients with BRCA1Mut carriers than those of BRCA2Mut carriers (OR: 2.663; 95% CI: 1.731–4.097; P = 0.211) or non-carriers (OR: 1.577; 95% CI: 1.067–2.331; P = 0.157). The data suggest that breast cancer patients with BRCA1Mut are more likely to have TNBC, high nuclear grade, and larger tumor burden.

Abstract 1731: Preclinical evaluation of the anti-tumor activity of Fc-fused interleukin-7 in both monotherapy and combination therapy

Abstract A remarkable progress of cancer immunotherapy in a recent decade, including immune checkpoint blockades (ICB), has shed a new light on the medical treatment of cancer patients. These successes of immunotherapies affirm the notion that modulation of immune-related environment, although not directly targeting a tumor cell, might lead to a better efficacy for cancer treatment. Interleukine-7 (IL-7), a member of the common γ chain family cytokine, plays important roles in the development and homeostasis of lymphocytes in both mouse and human, in particular T lymphocytes. Positive effects of recombinant IL-7 on anti-tumor activity in preclinical models have placed IL-7 as a strong candidate for a novel immunotherapeutic agent in clinics; however, a short half-life of recombinant protein has remained a challenge. Here, we investigated anti-tumor effects in mice of the long-acting form of recombinant human IL-7 fused with hybrid Fc (IL-7-hyFc) in syngeneic tumor models. A dramatic inhibition of tumor growth was achieved when IL-7-hyFc is given in a single subcutaneous injection with palpable tumor burdens. IL-7-hyFc administration significantly enhanced the expression level of CXCR3 on T cells and the frequency of CD8+ tumor-infiltrating lymphocytes (TILs). Of interest, the fraction of PD-1+CD8+ TILs was decreased by IL-7-hyFc, with the cell surface level of PD-1 being diminished. Therefore, IL-7-hyFc is able to expand tumor antigen specific CD8+ effector T cells, resulting in the enhanced infiltration and functional recuperation of TILs. Nonetheless, the tumor growth inhibition by IL-7-hyFc was not observed in mice with large tumor burdens. To increase the therapeutic efficacy of IL-7-hyFc in this model, we combined single injection of the conventional chemotherapeutics cyclophosphamide (CTX) with a moderate dose in which CTX confers immunogenic tumor cell death without severely depleting immune compartment. The combinatorial treatment with IL-7-hyFc and CTX augmented the infiltration of CD8+ TILs, leading to an increased survival in a large established tumor model. In sum, IL-7-hyFc confers the effective anti-tumor responses through reconstructing CD8+ T lymphocytes; this activity was limited when the tumor burden was high but restored along with combination with the chemotherapeutics. Thus, these results imply that IL-7-hyFc can be applied to various cancer immunotherapy regimens as monotherapy or a combination partner with conventional and other immunotherapy, like ICB. Citation Format: Ji-Hae Kim, Donghoon Choi, Man Kyu Ji, Seat-byeul Jo, Han Wook Park, Yeon Kyung Oh, Youngmin Kim, Hyekang Kim, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Seung-Woo Lee. Preclinical evaluation of the anti-tumor activity of Fc-fused interleukin-7 in both monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1731.

Teen with Neurofibromatosis Type 1 Presents with Large Scrotal Mass and Large Tumor Burden

Teen with Neurofibromatosis Type 1 Presents with Large Scrotal Mass and Large Tumor Burden

Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis

Abstract Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe IBD. Inflammatory bowel diseases (IBD) increase the risk for colorectal cancer. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colon biopsies from patients with colorectal cancer. We investigated the role of pyrin in intestinal homeostasis in mice. Mefv−/− and C57/BL6 mice were subjected to azoxymethane - dextran sodium sulfate (AOM-DSS) model of colitis and tumorigenesis. Pyrin was expressed in colons of control mice and expression increased during chronic and acute inflammation. Mefv−/− mice developed more severe colitis than control mice, with a greater extent of epithelial hyperplasia and a larger tumor burden. Mefv−/− mice had increased epithelial permeability early during DSS administration and increased levels of inflammatory cytokines and chemokines during acute colitis. On the other hand, IL18, which depends on the inflammasome for maturation and release, was significantly lower in colons of Mefv−/− mice. Further, the inflammatory milieu in Mefv−/− mice was pro-tumorigenic with increased STAT3 activation, and stem cell activity in the colon and reduced cytotoxic T cell activation in draining lymph nodes and spleen. Administration of rIL18 to Mefv−/− mice reduced epithelial permeability, intestinal inflammation, the severity of colitis, and colon tumorigenesis. In conclusion, we found that pyrin (MEFV) is required for inflammasome activation and IL18 maturation, which promote intestinal barrier integrity and prevent colon inflammation and tumorigenesis.

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) Tcell therapy. In CAR Tcell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered. Despite a narrow range of affinity for BCMA, dramatic differences in CAR Tcell expansion were observed between unique scFvs in a repeat antigen stimulation assay. These results were confirmed by screening in a MM xenograft model, where only the top preforming CARs from the repeat antigen stimulation assay eradicated disease and prolonged survival. The results of this screening identified a highly effective CAR Tcell therapy with properties, including rapid invivo expansion (>10,000-fold, day 6), eradication of large tumor burden, and durable protection to tumor re-challenge. We generated a bicistronic construct including a second-generation CAR and a truncated-epithelial growth factor receptor marker. CAR Tcell vectors stemming from this work are under clinical investigation.

4:12 PM Abstract No. 369 Tumor progression and resection candidacy after portal vein embolization

To evaluate achievement of resection candidacy after portal vein embolization (PVE) as a function of tumor burden and cell type. 49 patients (mean age 64, 73% males) underwent PVE from 2008-16 to induce hypertrophy in inadequately sized future liver remnants (FLR). Patients had hepatocellular carcinoma (HCC, n = 13), metastatic neuroendocrine tumor (mNET, n = 4), metastatic colorectal cancer (mCRC, n = 17), or metastatic gall bladder/cholangiocarcinoma (GB/CC, n = 15). Pre- and post-PVE volumetric assessment was performed for tumor, embolized regions, and FLR. Tumor progression within embolized regions and FLR was measured, and clinical outcomes were evaluated. 17 (35%) patients failed to proceed to resection (HCC = 2 (15%), mNET = 2 (50%), mCRC = 8 (47%), GB/CC = 5 (33%), p = 0.2). Reasons for failure to achieve candidacy were tumor progression in 12 (mCRC = 8, GB/CC = 3, HCC = 1), clinical deterioration in 3 (mNET = 1, HCC = 1, GB/CC = 1), and inadequate FLR in 2 (mNET = 1, GB/CC = 1). Although adequate hypertrophy was achieved in most of the failure patients, (mean FLR hypertrophy of 42%, from 581 to 765 ml, p = 0.012), mean tumor volume also increased, from 306 to 535 ml, (p = 0.03). With progression encroaching or crossing the resection margin classified as ipsilateral progression, only a tiny fraction of the total tumor burden and progression occurred within the FLR (3 to 6 ml, p = 0.2). Tumor progression was the major factor for failure for mCRC, with significant increases in tumor burden (p = <0.001). mCRC patients who progressed and failed had larger baseline tumor burdens (416 vs 104 ml, p = 0.008). 32 (65%) patients were resected at a mean of 53 ± 19 d after PVE (mean FLR hypertrophy 67%, from 560 to 863 ml, p<.001), and no prohibitive change in tumor volume (339 to 337 ml, p = 0.9). Resected patients had improved overall survival (19 vs 9 mo, p = 0.018) PVE induces rapid FLR hypertrophy, but can also induce tumor progression preventing resection. Patients with mCRC and with large baseline tumor burdens are at highest risk of failure to achieve resection candidacy.

7,8-Dihydroxycoumarin exerts antitumor potential on DMBA-induced mammary carcinogenesis by inhibiting ERα, PR, EGFR, and IGF1R: involvement of MAPK1/2-JNK1/2-Akt pathway.

Breast cancer (BC) is a persistent and impulsive metabolic disorder with the highest prevalence in women, worldwide. 7,12-Dimethylbenz(a)anthracene (DMBA) is a potent polyaromatic hydrocarbon (PAH)-based carcinogen producing mammary carcinomas in rats resembling the human hormone-dependent BC. 7,8-Dihydroxycoumarin (78DC) is a coumarin derivative that possesses diversified and favorable pharmacology profile to be considered in anticancer research against various malignancies. The present study was intended to investigate the antiproliferative and chemotherapeutic potentials of 78DC (20, 40, and 80mg/kg BW) against DMBA (20mg in olive oil)-induced mammary carcinoma Sprague-Dawley rats. We established the in silico approach for evaluation of the effect of 78DC on hormonal (estrogen receptor-α (ERα), progesterone receptor (PR)), growth factor receptors (EGFR and IGFR), 17β-hydroxysteroid dehydrogenase type 1 (17β-HD1), and aromatase. Effect of 78DC on estrogen synthesis, tumor growth, proliferation markers (Ki-67 and PCNA), cytokines (IL-10, IL-1β, IL-12), chemokine (MCP-1), and cellular expressions of ERα, PR, EGFR, IGF1R, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase was evaluated in mammary carcinoma bearing SD rats. DMBA induces large tumor burden and histological alterations in mammary gland with a subsequent increase in ERα, PR, EGFR, IGF1R, Ki-67, proliferating cell nuclear antigen (PCNA), cytokines, and chemokine expressions. This was also correlated with the changes in rapid cell differentiation and proliferation. In contrast, 78DC treatment to the cancer-bearing animals abbreviated these changes and revealed to possess antitumorigenic and antiproliferative potentials. Further, a significant decrease in expressions of ERα, PR, EGFR, IGFR, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase signifies a reduction in estrogen sensitivity and secondary signaling pathways that may contribute to the prevention of tumor growth. The current findings revealed that 78DC potentially reduce cancer cell proliferation and reverted mammary cancer-induced changes in experimental animals in a dose-dependent manner.

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.

Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis

Inflammatory bowel diseases (IBD)increase risk for colorectal cancer. Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe IBD. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colonbiopsies from patients with IBD. We investigated therole of pyrin in intestinal homeostasis in mice. Mefv-/- mice and C57/BL6 mice (controls) were given azoxymethane followed by multiple rounds of dextran sodium sulfate (DSS) to induce colitis and tumorigenesis. In some experiments, Mefv-/- mice were given injections of recombinant interleukin 18 (rIL18) or saline (control) during DSS administration. Colon tissues were collected at different time points during colitis development and analyzed by histology, immunohistochemistry, immunoblots, or ELISAs (to measure cytokines). Spleen and mesenteric lymph node were collected, processed, and analyzed by flowcytometry. Colon epithelial permeability was measured in mice with colitis by gavage of fluorescent dextran and quantification of serum levels. MEFV was expressed in colons of control mice and expression increased during chronic and acute inflammation; high levels were detected in colon tumor and adjacent non-tumor tissues. Mefv-/- mice developed more severe colitis than control mice, with a greater extent of epithelial hyperplasia and a larger tumor burden. Levels of inflammatory cytokines (IL6) and chemokines were significantly higher in colons of Mefv-/- mice than control mice following colitis induction, whereas the level IL18, which depends on the inflammasome for maturation and release, was significantly lower in colons of Mefv-/- mice. Mefv-/- mice had increased epithelial permeability following administration of DSS than control mice, and loss of the tight junction proteins occludin and claudin-2 from intercellular junctions. STAT3 was activated (phosphorylated) in inflamed colon tissues from Mefv-/-, which also had increased expression of stem cell markers (OLFM4, BMI1, and MSI1) compared with colons from control mice. Administration of rIL18 to Mefv-/- mice reduced epithelial permeability, intestinal inflammation, the severity of colitis, and colon tumorigenesis. In studieswith DSS-induced colitis, we found that pyrin (MEFV)is required for inflammasome activation and IL18 maturation, which promote intestinal barrier integrity andprevent colon inflammation and tumorigenesis. Strategies to increase activity of MEFV or IL18 might be developed for thetreatment of IBD and prevention of colitis-associated tumorigenesis.

Treatment for Malignant Pheochromocytomas and Paragangliomas: 5 Years of Progress

The purpose of this manuscript is to review the progress in the field of therapeutics for malignant pheochromocytomas and sympathetic paraganglioma (MPPG) over the past 5years. The manuscript will describe the clinical predictors of survivorship and their influence on the first TNM staging classification for pheochromocytomas and sympathetic paragangliomas, the treatment of hormonal complications, and the rationale that supports the resection of the primary tumor and metastases in patients with otherwise incurable disease. Therapeutic options for patients with bone metastasis to the spine will be presented. The manuscript will also review chemotherapy and propose a maintenance regimen with dacarbazine for patients initially treated with cyclophosphamide, vincristine, and dacarbazine. Finally, the manuscript will review preliminary results of several phase 2 clinical trials of novel radiopharmaceutical agents and tyrosine kinase inhibitors. MPPGs are very rare neuroendocrine tumors. MPPGs are usually characterized by a large tumor burden, excessive secretion of catecholamines, and decreased overall survival. Recent discoveries have enhanced our knowledge of the pathogenesis and phenotypes of MPPG. This knowledge is leading to a better understanding of the indications and limitations of the currently available localized and systemic therapies as well as the development of phase 2 clinical trials for novel medications.

Surgical Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. In select patients, surgical treatment in the form of either resection or transplantation offers a curative option. The aims of this review are to (1) review the current American Association for the Study of Liver Diseases/European Association for the Study of the Liver guidelines on the surgical management of HCC and (2) review the proposed changes to these guidelines and analyze the strength of evidence underlying these proposals. Three authors identified the most relevant publications in the literature on liver resection and transplantation for HCC and analyzed the strength of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. In the United States, the liver allocation system provides priority for liver transplantation to patients with HCC within the Milan criteria. Current evidence suggests that liver transplantation may also be indicated in certain patient groups beyond Milan criteria, such as pediatric patients with large tumor burden or adult patients who are successfully downstaged. Patients with no underlying liver disease may also benefit from liver transplantation if the HCC is unresectable. In patients with no or minimal (compensated) liver disease and solitary HCC ≥2 cm, liver resection is warranted. If liver transplantation is not available or contraindicated, liver resection can be offered to patients with multinodular HCC, provided that the underlying liver disease is not decompensated. Many patients may benefit from surgical strategies adapted to local resources and policies (hepatitis B prevalence, organ availability, etc). Although current low-quality evidence shows better overall survival with aggressive surgical strategies, this approach is limited to select patients. Larger and well-designed prospective studies are needed to better define the benefits and limits of such approach.

The evolving role of cytopathology in the era of neoadjuvant chemotherapy for the accurate pathologic diagnosis of epithelial ovarian cancer.

The evolving role of cytopathology in the era of neoadjuvant chemotherapy for the accurate pathologic diagnosis of epithelial ovarian cancer.

Abstract 4805: The role of exosomes in fibrosarcoma progression

Abstract Among pediatric cancers, sarcomas, especially those with large tumor burdens and metastatic disease, often result in poor outcome. Thus, new treatments are urgently needed to inhibit tumor progression, prevent metastasis, and improve overall survival. To understand the mechanisms driving sarcoma progression, we employed two mouse fibrosarcoma cell lines that display different growth phenotypes when transplanted into syngeneic immune competent mice. Progressor fibrosarcomas evade detection by the immune system and develop large tumor burdens, while regressor fibrosarcomas regress shortly after a period of limited tumor growth. This difference in the growth phenotype is mediated in part by immune cells, but the mechanisms by which progressor and regressor cells influence immune cell activity are not fully elucidated. Our research has focused on exosomes, 50-100 nm secreted nanovesicles, that contain bioactive cargoes and have emerged as mediators of intercellular communication between various cells. Here, we hypothesize that fibrosarcoma exosomes determine the aggressiveness of the disease by either educating tumor cells themselves or altering interactions with host cells. To investigate the role of fibrosarcoma exosomes, we first educated regressor tumor cells with progressor exosomes for 3 weeks in vitro, and vice versa. Upon in vivo inoculation, progressor cells conditioned with regressor cell-derived exosomes grew significantly slower compared to untreated progressor cells. In contrast, regressor cells educated with progressor exosomes did not regress and overgrew significantly compared to untreated regressor cells. These results indicate that exosomes have an ability to reprogram a tumor phenotype. To determine if fibrosarcoma exosomes specifically impact the host, we evaluated whether conditioning naïve mice with progressor exosomes alters in vivo growth of regressor tumor cells injected after three weeks of education. Twenty percent of regressor tumors continued to grow following progressor exosome education, while all tumors regressed in the control PBS group. These data suggest that exosomes also play an important role in the interaction with the host cells influencing tumor growth and disease progression. Next, to determine which exosomal cargo may mediate these effects, we sought to characterize the proteome of exosomes from progressor and regressor cells using mass spectrometry. We found basigin, also known as CD147, a transmembrane embryonic glycoprotein reported to regulate cell proliferation, tumor migration and metastasis as one of the candidate proteins highly expressed in progressor-derived exosomes. We conclude that exosomes derived from fibrosarcoma progresssors and regressors can alter the tumor phenotype both directly and indirectly. Exosomal cargo, such as basigin, may mediate the aggressive behavior of tumor cells, making it a potential therapeutic target to inhibit fibrosarcoma progression. Citation Format: Miho Nakajima, Stephen C. Searles, Ayuko Hoshino, Katherine M. Offer, Candia M. Kenific, Jack D. Bui, David C. Lyden. The role of exosomes in fibrosarcoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4805. doi:10.1158/1538-7445.AM2017-4805

Venetoclax for the treatment of patients with chronic lymphocytic leukemia.

Venetoclax is a potent, selective inhibitor of BCL-2, a key regulator of the intrinsic pathway of apoptosis. In preclinical studies, venetoclax bound to BCL-2 with high affinity and rapidly induced apoptosis in chronic lymphocytic leukemia (CLL) cells. In early-phase clinical trials in CLL, venetoclax treatment led to tumor lysis syndrome in some patients with a large tumor burden, but this risk was subsequently mitigated by a revised study design that included lower initial dosing with intrapatient dose ramp up and close tumor lysis syndrome monitoring and prophylaxis. Other toxicities, such as neutropenia and gastrointestinal adverse events, were manageable. Venetoclax monotherapy resulted in durable and deep responses in patients with relapsed, refractory CLL, including for those with deletion 17p, leading to the approval of venetoclax by the US FDA for relapsed or refractory deletion 17p CLL, and recently to additional approvals in Europe and Canada. Trials also suggest that venetoclax induces deeper and more durable responses when used in combination with rituximab, and combination studies with other agents are ongoing. Phase III trials are also underway, and will provide data on the efficacy and safety of venetoclax in combination with monoclonal antibodies and targeted therapies in larger patient populations.

Pre-therapeutic factors for predicting survival after radioembolization: a single-center experience in 389 patients

To determine pre-therapeutic predictive factors for overall survival (OS) after yttrium (Y)-90 radioembolization (RE). We retrospectively analyzed the pre-therapeutic characteristics (sex, age, tumor entity, hepatic tumor burden, extrahepatic disease [EHD] and liver function [with focus on bilirubin and cholinesterase level]) of 389 consecutive patients with various refractory liver-dominant tumors (hepatocellular carcinoma [HCC], cholangiocarcinoma [CCC], neuroendocrine tumor [NET], colorectal cancer [CRC] and metastatic breast cancer [MBC]), who received Y-90 radioembolization for predicting survival. Predictive factors were selected by univariate Cox regression analysis and subsequently tested by multivariate analysis for predicting patient survival. The median OS was 356days (95% CI 285-427 days). Stable disease was observed in 132 patients, an objective response in 71 (one of which was complete remission) and progressive disease in 122. The best survival rate was observed in patients with NET, and the worst in patients with MBC. In the univariate analyses, extrahepatic disease (P < 0.001), large tumor burden (P = 0.001), high bilirubin levels (>1.9mg/dL, P < 0.001) and low cholinesterase levels (CHE <4.62 U/I, P < 0.001) at baseline were significantly associated with poor survival. Tumor entity, tumor burden, extrahepatic disease and CHE were confirmed in the multivariate analysis as independent predictors of survival. Sex, applied RE dose and age had no significant influence on OS. Pre-therapeutic baseline bilirubin and CHE levels, extrahepatic disease and hepatic tumor burden are associated with patient survival after RE. Such parameters may be used to improve patient selection for RE of primary or metastatic liver tumors.

Abstract No. 483 - Drug eluting bead chemoembolization for neuroendocrine tumor metastases: risk factors for biliary toxicity

To evaluate possible risk factors contributing to biliary toxicity after drug-eluting bead transarterial chemoembolization (DEB-TACE) treatment of neuroendocrine tumor (NET) hepatic metastases. 13 patients (mean age: 65.8, 55% males) who underwent 23 DEB-TACE treatments between 2011-2015 for hepatic NET metastases from gut (n = 4), pancreas (n = 6), lung (n = 2) & unidentified (n = 1) primary sites were reviewed retrospectively. Tumor characteristics (grade, burden, arterial supply), previous therapeutic history (systemic chemotherapy and targeted therapies, peptide radiotherapy, resection of primary tumor), and clinical outcomes were evaluated. Because of recent published warnings, special emphasis was placed on biliary toxicity, including biliary ductal dilatation, biloma and/or abscess formation, and biochemical toxicity. 7 patients developed biloma or abscess but only 1 required hospitalization and percutaneous drainage. 10 patients developed focal intrahepatic ductal dilatation. Biliary complications were associated with lower tumor burden (P = 0.036), and prior biliary/pancreatic surgical interventions (P = 0.021). 3 patients demonstrated grade 3/4 alkaline phosphatase elevation, but none had severe elevations of serum bilirubin. No relationship was found with catheterization or treatment selectivity (segmental/lobar) or tumor grade. Large tumor burden and its covariables of large administered dose of doxorubicin (>75 mg) and necessity for supplemental bland embolization, were found to reduce risk of biliary complications (P = 0.033). Prior systemic treatment with antiangiogenic drugs also decreased the risk of biliary complications (P = 0.037). DEB-TACE showed median time to progression (TTP) of 13.7 months and overall survival (OS) of 56.7 months. DEB-TACE is an effective option for treatment of NET hepatic metastases, but is associated with a high incidence of biliary complications. It appears to be safest for patients with large tumor burdens who have undergone previous treatment by systemic antiangiogenic drugs, perhaps due to minimized nontarget deposition.

Prevention and treatment of tumor lysis syndrome, and the efficacy and role of rasburicase.

Tumor lysis syndrome (TLS) is a potentially life-threatening condition that occurs in oncologic and hematologic patients with large tumor burden, either due to cytotoxic therapy or, less commonly, spontaneously because of massive tumor cell lysis. TLS is clinically characterized by acute renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. While limited options are available for treating TLS, identifying patients at high risk for developing TLS and prevention in high-risk patients remain an important aspect in the treatment of cancer patients. In general, treatment of TLS consists of intensive hydration, stimulation of diuresis, and, more specifically, in the use of allopurinol and rasburicase. Rasburicase, a recombinant urate oxidase, rapidly and effectively reduces hyperuricemia, which subsequently significantly decreases the risk of acute renal failure and other clinical manifestations of TLS. For this review, a comprehensive literature search using the term “tumor lysis syndrome” and/or “rasburicase” was performed considering articles listed in MEDLINE. Incidence, prevention, and therapy of TLS with a special focus on the role of rasburicase are discussed. We evaluated 120 relevant articles including 35 case reports, 32 clinical trials, and 14 meta-analyses.

Meeting Highlights: The Second Consensus Conference for Breast Cancer Treatment in Korea.

The Korean clinical practice guideline recently developed by the Korean Breast Cancer Society to address the national clinical situation is currently under revision ahead of a seventh recommendation. A second consensus conference was held to further develop this guideline by soliciting opinions regarding important issues related to surgery, radiotherapy, and medical oncology. Several issues were discussed, and the discussion progressed to pros and cons in the context of cases in various clinical situations. The panels discussed and voted on issues regarding surgical treatment for non-axillary regional lymph nodes, regional nodal irradiation of pN1 disease, and ovarian functional suppression (OFS) as an adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer. Regarding the surgical treatment of non-axillary regional lymph node, most panelists agreed with the recommendation of preoperative chemotherapy and postoperative radiotherapy for patients with biopsy-diagnosed metastases, whereas surgery or radiotherapy of non-axillary regional lymph nodes was suggested for clinical partial responders. Discussions on radiotherapy addressed the need for adjuvant radiotherapy and radiation field of regional lymph node in the context of various N1 breast cancer cases. The participants reached a consensus to recommend that N1 patients should receive regional nodal irradiation for a large tumor burden (e.g., three positive nodes, perinodal extension, or large primary tumor). Finally, the panels favored OFS in addition to endocrine therapy for premenopausal women with high risk factors such as a large tumor size, involvement of more than three nodes, and a high histologic grade.

Phase I/II trial evaluating concurrent carbon-ion radiotherapy plus chemotherapy for salvage treatment of locally recurrent nasopharyngeal carcinoma

BackgroundAfter definitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma (NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present significant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can benefit from these treatments. Re-irradiation with X-ray—based intensity-modulated radiotherapy (IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radio-resistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy (CIRT). In addition, CIRT is a high linear energy transfer (LET) radiation and provides an increased relative biological effectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 GyE (gray equivalent), at 2.5 GyE per daily fraction, was well tolerated in patients who were previously treated for NPC with a definitive dose of IMXT. The short-term response rates at 3–6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can benefit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the benefits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results.Methods and designThe maximal tolerated dose (MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 GyE (2.5 GyE × 21–26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Efficacy in terms of overall survival (OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%.ConclusionsRe-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate efficacy but causes potentially severe toxicities. Improved outcomes in terms of efficacy and toxicity profile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.

Irradiance-dependent UVB Photocarcinogenesis.

Ultraviolet B (UVB) radiation from the sun may lead to photocarcinogenesis of the skin. Sunscreens were used to protect the skin by reducing UVB irradiance, but sunscreen use did not reduce sunburn episodes. It was shown that UVB-induced erythema depends on surface exposure but not irradiance of UVB. We previously showed that irradiance plays a critical role in UVB-induced cell differentiation. This study investigated the impact of irradiance on UVB-induced photocarcinogenesis. For hairless mice receiving equivalent exposure of UVB radiation, the low irradiance (LI) UVB treated mice showed more rapid tumor development, larger tumor burden, and more keratinocytes harboring mutant p53 in the epidermis as compared to their high irradiance (HI) UVB treated counterpart. Mechanistically, using cell models, we demonstrated that LI UVB radiation allowed more keratinocytes harboring DNA damages to enter cell cycle via ERK-related signaling as compared to its HI UVB counterpart. These results indicated that at equivalent exposure, UVB radiation at LI has higher photocarcinogenic potential as compared to its HI counterpart. Since erythema is the observed sunburn at moderate doses and use of sunscreen was not found to associate with reduced sunburn episodes, the biological significance of sunburn with or without sunscreen use warrants further investigation.