Complete Tumor Control Research Articles

Long-term (20-year) real-world outcomes of intravenous chemotherapy (chemoreduction) for retinoblastoma in 964 eyes of 554 patients at a single centre

BackgroundIntravenous chemotherapy (IVC) remains an important globe salvage therapy for retinoblastoma.MethodsEvaluation of long-term globe salvage at 5, 10, 15 and 20 years following frontline IVC for retinoblastoma.ResultsOf 994 eyes, comparison...

Preclinical Development of an Actinium-225-Labeled Antibody Radio-Conjugate Directed Against CD45 for Targeted Conditioning and Radioimmunotherapy

Introduction Radiolabeled CD45 antibodies have demonstrated clinical promise as targeted conditioning agents prior to bone marrow transplant (BMT) as a better tolerated and potentially more effective alternative to chemotherapy and/or total body irradiation myeloablative conditioning regimens. CD45 is expressed on all immune cells, including hematopoietic stem cells and both precursor and mature lymphoid and myeloid cells, making it an ideal antigen for directing targeted radiation for conditioning. It is also highly expressed on most hematological cancers, offering the potential for a substantial anti-tumor effect. We describe the preclinical development of a novel anti-CD45 antibody radio-conjugate that consists of the pan-CD45 antibody BC8 labeled with the potent alpha emitter Actinium-225 (225Ac). Methods and Results The monoclonal antibody BC8 (apamistamab) was first conjugated with the DOTA chelator and then labeled with 225Ac, achieving a labeling efficiency typically greater than 80%. Furthermore, 225Ac-BC8 was shown to be stable and retain selective immunoreactivity to CD45+ cells following conjugation and labeling. To evaluate the anti-tumor potency of 225Ac-BC8, two CD45+ human multiple myeloma (MM) cell lines with high or low relative CD45 antigen density, U266 and H929, respectively, (Collette, et al. 2007 Eur. Cytokine Netw. 18:120-126) were tested by cell cytotoxicity assay and achieved greater than 90% cell killing of both lines. To assess the therapeutic potential of 225Ac-BC8, its anti-tumor activity was tested in xenograft models of H929 and U266. NOD-SCID mice bearing established tumors received a single dose of 300 nCi of 225Ac-BC8, 300 nCi of an irrelevant radio-conjugate 225Ac-18B7, naked BC8 antibody, or no treatment. In both models, 225Ac-BC8 exerted complete and durable tumor control for the duration of study. None of the control groups exhibited any anti-tumor effect. Favorable biodistribution results were obtained with SPECT/CT imaging using an 111In-labeled mouse pan CD45 surrogate antibody 30F11 (111Ac-30F11), since BC8 does not cross react with mouse CD45. 225Ac-30F11 is a useful surrogate molecule to study the tolerability and myeloablative properties of 225Ac-anti-CD45 antibodies for targeted conditioning prior to donor BMT, using B6-Ly5b donor cells in B6-Ly5a mice. Results of ongoing conditioning studies will be presented. Conclusions The pan-CD45 antibody BC8 was shown to be efficiently conjugated and labeled with the potent alpha emitter 225Ac to mediate robust and selective killing of CD45+ MM cells and xenografts. Biodistribution analysis confirmed selective uptake into organs of the immune system including homing to BM. These preclinical data and ongoing myeloablative/BM reconstitution studies support the development of 225Ac-BC8 as a novel potent and safe targeted conditioning approach for BMT.

Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma.

Retinoblastoma is a rare intraocular malignancy in children. Current treatments have many adverse effects. New therapeutic approaches like intravitreal injections of chemotherapies are currently being developed but their toxicities need to be evaluated on animal models. This study compares the efficacy and toxicity of intravitreal melphalan, topotecan and carboplatin, alone or in combination (sequential administration), in the LHBetaTag retinoblastoma mice. Mice were divided into nine groups: control, carboplatin 1.5 and 4 μg, melphalan 0.1 and 1 μg, topotecan 0.1 and 1 μg, carboplatin 4 μg/topotecan 0.1 μg and melphalan 1 μg/topotecan 0.1 μg. The follow-up was performed using fundus imaging and optical coherence tomography combined with histopathological analysis. Absence of tumour and presence of calcified tumours were the criteria for therapeutic response assessment. Ocular complications were assessed after four weekly injections. Retinal toxicity was defined by the decrease of retinal thickness and of the number of retinal layers. Topotecan was inactive on retinal tumours. Melphalan (1 μg) led to a complete tumour control in 91.7% of eyes. Carboplatin strongly decreased the tumour burden (85.7-93.8% of eyes without retinal tumour). The intravitreal injection itself led to ocular complications (25% of media opacities and 45.7% of retinal detachment). Only melphalan at 1 μg showed a strong retinal toxicity. The two combinations showed a good efficacy in reducing the number of eyes with retinal tumours with a reduced retinal toxicity. This preclinical study suggests that intravitreal injection of carboplatin has a low toxicity and could be evaluated in clinical practice to treat patients suffering from retinoblastoma.

Preclinical Development of an Actinium-225-Labeled Antibody Radio-Conjugate Directed Against CD45 for Targeted Conditioning and Radioimmunotherapy

Introduction: Radiolabeled CD45 antibodies have demonstrated clinical promise as targeted conditioning treatments prior to bone marrow transplant (BMT) as a better tolerated and potentially more effective alternative to harsh chemotherapy and/or total body irradiation regimens for myeloablative conditioning. CD45 is expressed on all immune cells, including hematopoietic stem cells and both precursor and mature lymphoid and myeloid cells, with an average copy number up to 200,000 molecules per cell, making it an ideal antigen for directing targeted radiation for conditioning. It is also highly expressed on most lymphomas and leukemias, and approximately 50% of multiple myeloma, further offering the potential for mediating a substantial anti-tumor effect in treated patients. We describe the preclinical development of a novel anti-CD45 antibody radio-conjugate (ARC) that harnesses the power of alpha radiation by arming the pan-CD45 antibody BC8 with Actinium-225 (225Ac). 225Ac is a potent radionuclide with high linear energy transfer (80-100 keV/μm) yet short path length (50-80 μm) to deliver significantly more lethal double strand DNA breaks per alpha track than beta particles. In addition, the use of 225Ac for targeted conditioning has advantages of safe handling and ease of use and a long 10 day half-life that enables flexibility in preparation and use. Methods and Results: To generate 225Ac-BC8, the monoclonal antibody was first conjugated with the DOTA chelator, then labeled with 225Ac, achieving a labeling efficiency typically greater than 80%. 225Ac-BC8 was subsequently purified to high radiochemical purity by column chromatography. Using human CD45+ Ramos lymphoma cell line and EL4 as negative control, 225Ac-BC8 was shown to be stable and retain selective immunoreactivity following conjugation and labeling. To evaluate the anti-tumor potency of 225Ac-BC8, two CD45+ human multiple myeloma (MM) cell lines with high or low relative CD45 antigen density, U266 and H929, respectively, (Collette, et al. 2007) were tested by cell cytotoxicity assay. Following transient exposure (4 or 12 hours) to 225Ac-BC8, the ARC demonstrated potent dose-dependent MM cell killing 72 hours post-treatment, achieving greater than 90% cytotoxicity of both cell lines. To further assess the therapeutic potential of 225Ac-BC8, its anti-tumor activity was tested in subcutaneous (s.c.) xenograft models of H929 and U266. NOD-SCID mice bearing established s.c. tumors were randomized to receive a single dose of 300 nCi of 225Ac-BC8, 300 nCi of an irrelevant radio-conjugate 225Ac-18B7, naked BC8 antibody, or no treatment control. In both models, 225Ac-BC8 exerted complete and durable tumor control for the duration of study. None of the control groups exhibited any anti-tumor effect. Studies to evaluate 225Ac-BC8 in models of CD45+ lymphoma are ongoing. Since BC8 does not cross-react with mouse CD45 and only weakly with macaque CD45, biodistribution, dosimetry and imaging analysis was performed in mice using radio-labeled anti-mouse pan-CD45 surrogate antibody 30F11. SPECT/CT imaging and biodistribution was performed with 111In-labeled 30F11. Following IV administration, 111In-CD45 (30F11) rapidly cleared from the blood and accumulated in immune system organs including spleen, bone marrow, and lymph node. Dosimetry calculations for 225Ac-CD45 (30F11) were determined for absorbed dose to target organs. Only modest uptake was noted in the kidney, but significant uptake occurred in liver, the major site for catabolism of full-length antibodies. 225Ac-CD45 (30F11) is a useful molecule to study the tolerability and myeloablative properties of 225Ac-CD45 antibody for targeted conditioning prior to donor BMT, using B6-Ly5b donor cells in B6-Ly5a mice. Results of ongoing studies will also be presented. Conclusions: The pan-CD45 antibody BC8 was shown to be efficiently conjugated and labeled with the potent alpha emitter 225Ac to mediate robust and selective killing of CD45+ MM cells and xenografts. Biodistribution analysis confirmed selective uptake into organs of the immune system including homing to BM. Supported by ongoing myeloablative/BM reconstitution studies, these preclinical data support the development of 225Ac-BC8 as a novel potent and safe targeted conditioning approach for BMT. Reference: Collette, et al., (2007). Eur. Cytokine Netw. 18:120-126. Disclosures Ludwig: Actinium Pharmaceuticals: Employment, Equity Ownership. Dawicki:Actinium Pharmaceuticals: Research Funding. Geoghegan:Actinium Pharmaceuticals: Employment. Liang:Actinium Pharmaceuticals: Employment. Seth:Actinium Pharmaceuticals: Employment, Equity Ownership. Gokhale:Actinium Pharmaceuticals: Employment. Berger:Actinium Pharmaceuticals, Inc: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment. Dadachova:Actinium Pharmaceuticals: Consultancy, Research Funding; RadImmune Therapeutics: Consultancy, Research Funding.

Abstract 1466: Combination immunotherapy successfully control tumor growth in a transgenic mouse model

Abstract The use of checkpoint inhibitor anti-PD1 has achieved significant clinical benefit, in recurrent and metastatic head and neck cancer patients, where the overall response rate is between 16-20%. The use of antigen-specific cancer vaccine to increase the level of cytotoxic T cells is believed to work synergistically with anti-PD1. In this study, we evaluated the efficacy of antigen-specific DNA vaccine when it’s used in combination with anti-PD1. The B6.Cg-Tg(HLA-A/H2-D)2Enge/J mice bearing established tumours overexpressing the tumour antigen were vaccinated either with anti-PD1, DNA vaccine or anti-PD1 in combination with DNA vaccine. Tumour volume was monitored and antigen-specific immune responses were evaluated at the endpoint. Our data demonstrated DNA vaccine induced antigen-specific immune responses and animals vaccinated with DNA vaccine harboured smaller tumour volume compared to controls. Significantly, animals that received DNA vaccine expressed consistently higher levels IFN-γ and resulted in the upregulation of PD1 compared to control animals. We then demonstrated mice vaccinated with both DNA vaccine and anti-PD1 had near to complete tumour control, indicating a synergistic effect of DNA vaccine with anti-PD1. Animals treated with DNA vaccine in combination with anti-PD1 also have better overall survival. Importantly, these animals showed increased antigen-specific responses by the ELISPOT assay. In summary, our data suggest antigen-specific DNA vaccine works synergistically with anti-PD1 and conferred an excellent tumour control; this opens up a new opportunity of combinatory immunotherapy that might benefit a wider population of patients in an antigen-specific manner. Citation Format: Kue Peng Lim, Syafinaz Zainal, Natasha Zulaziz, Chai Phei Gan, San Jiun Chai, Bryan Kit Weng Lye, Chuan Wang, Ruhcha V. Sutavani, Christian Ottensmeier, Emma King, Gareth Thomas, Natalia Savelyeva, Sok Ching Cheong. Combination immunotherapy successfully control tumor growth in a transgenic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1466.

IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration.

Paraneoplastic neurological disorders result from an autoimmune response against neural self-antigens that are ectopically expressed in neoplastic cells. In paraneoplastic disorders associated to autoantibodies against intracellular proteins, such as paraneoplastic cerebellar degeneration (PCD), current data point to a major role of cell-mediated immunity. In an animal model, in which a neo-self-antigen was expressed in both Purkinje neurons and implanted breast tumor cells, immune checkpoint blockade led to complete tumor control at the expense of cerebellum infiltration by T cells and Purkinje neuron loss, thereby mimicking PCD. Here, we identify 2 potential therapeutic targets expressed by cerebellum-infiltrating T cells in this model, namely α4 integrin and IFN-γ. Mice with PCD were treated with anti-α4 integrin antibodies or neutralizing anti-IFN-γ antibodies at the onset of neurological signs. Although blocking α4 integrin had little or no impact on disease development, treatment using the anti-IFN-γ antibody led to almost complete protection from PCD. These findings strongly suggest that the production of IFN-γ by cerebellum-invading T cells plays a major role in Purkinje neuron death. Our successful preclinical use of neutralizing anti-IFN-γ antibody for the treatment of PCD offers a potentially new therapeutic opportunity for cancer patients at the onset of paraneoplastic neurological disorders.

Outcomes of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Included in Phase I Clinical Trials

INTRODUCTIONThe phase 1 selection for clinical trials of patients with relapsed or refractory Diffuse Large-B cell lymphoma (R/R DLBCL) with a potentially rapid tumor growth is a challenge. Prognostics' factors identification could help to better orient patients in appropriate clinical trials. This study is focused on DLBCL to evaluate their outcomes in phase I clinical trials. Our main objectives were to identify prognostic factors, attest the investigational drugs' safety and perform a preliminary assessment of drugs' efficacy.METHODAll consecutive patients with R/R DLBCL included in phase I clinical trial at a single cancer center in France between 2008 and 2017. If a given patient had participated in several phase I clinical trial, only the data from his first trial were examined. The patients' and DLBCL characteristics, the safety data and the efficacy outcomes were recorded. Reponses were assessed according to the International Harmonization Project in Lymphoma Cheson 2007 criteria. Overall responses rates (ORR) included partial responses (PR) and complete response (CR) and tumor control rates included overall responses and stable disease (SD).RESULTSA total of 101 patients (males: 63,4%) with R/R DLBCL were included in a panel of 21 clinical trials. The median age was 64 (range 21-86). Before their inclusion in a phase I trial, patients had received a median of 3 (1-7) lines of treatment and 25,7% of patients had undergone an autologous stem cell transplantation. At the cute-off date, 5 of the 101 patients (4,95%) were still taking the investigational drug. The median progression-free survival and overall survival (OS) were 1,8 and 9,7 months. High-grade toxicity (grade 3 or higher) occurred in 47 of the 101 patients (46,5%), and was related to the investigational drug in 29 of these cases (61,7%). The most important drugs-related toxicity was a hematological toxicity (neutropenia and thrombocytopenia) for 79,3% of patients, other toxicities were digestive toxicity (5,9%), cutaneous toxicity (2,9%), hepatotoxicity (2,9%) and pneumopathy (2,9%). Dose-limiting toxicity (DLT) was experienced by 7 (6,9%) of the 101 patients. The time from D1C1 (day 1, cycle 1) to the occurrence of high-grade toxicity was 1,2 months (range 0,2-9,5). High-grade toxicity occurred during the DLT period (< 6 weeks) for 27 of the 46 patients (58,7%) and after the DLT period in the remaining 19 (41,3%) patients.Factors associated with poor overall survival (overall survival inferior to the median OS) were Ann Arbor staging (73.6% of poor OS patients (< 9.7 months) with a performance status at 4), serum albumin (30.2% of poor OS patients with a low rate of serum albumin ≤ 35 g/L), serum LDH (79.2% of poor OS patients with a high rate of serum LDH > 250 U/L) and progressive disease (90.6% of poor OS patients had a trial withdrawal because of progression). The overall objective response and disease control rates were 25% and 43%. The median trial duration was 1.9 months and were respectively 12,1 and 5,5 months for responders (PR and CR) and controlled patients (PR and CR and SD). 36.6% of patients were prematurely withdrawing of study (before weeks 6). Factors associated with premature withdrew were performance status at baseline (67.6% of early withdrawal patients at performance status 1); Ann Arbor staging (67.6% of early withdrawal patients at Ann Arbor stage 4); serum LDH (73% of early withdrawal patients with a high rate of serum LDH > 250 U/L) and serum albumin (35,1% of early withdrawal patients with a low rate of serum albumin ≤ 35 g/L).CONCLUSIONHigh-grade toxicity occurred after the DLT period in 41.3% of patients with R/R DLBCL, suggesting that the conventional concept of dose-limiting toxicity should be redefined in the era of modern cancer therapies. Besides, even if the phase 1 selection for clinical trials is very selective, it's necessary to better orient patients in hematology. In fact, 36.6% of patients were prematurely withdrawing of study which could be anticipated thanks to the identification of prognostics' factors. Although the objective response is only a secondary endpoint in phase I clinical trials, the median duration of participation in trials (almost one year for responders and 5.5 months for controlled patients) are relevant for some new possibilities of therapeutics in the field of early drugs clinical trials. [Display omitted] DisclosuresRibrag:NanoString Technologies: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy; MSD: Honoraria; Roche: Honoraria, Other: travel; Infinity: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Amgen: Research Funding; Servier: Consultancy, Honoraria; pharmamar: Other: travel; Gilead: Consultancy, Honoraria; argenX: Research Funding.

Super-Thick Amniotic Membrane Graft for Ocular Surface Reconstruction

The purpose of this study was to evaluate super-thick amniotic membrane grafts (ST-AMGs) for ocular surface reconstruction. Retrospective, interventional case series. This was a single-center study of clinical practice that included select patients with typically large ocular surface abnormalities that required reconstruction. The intervention studied was surgical insertion of a ST-AMG for reconstruction or repair of the ocular surface. Main outcome measures included intraoperative handling, graft position at 1week post implantation, graft dissolution at 3weeks, epithelialization of the ocular surface and symblepharon. Eleven ST-AMGs were implanted after resection with cryotherapy: 5 conjunctival melanoma, 4 squamous cell carcinoma, 1 sebaceous carcinoma, and 1 atypical pterygium. In addition, 1 was implanted for scleral necrosis. ST-AMGs were up to nine times thicker than standard amniotic grafts and were therefore amenable to both running and interrupted 7-0 Vicryl sutures without cheese-wiring. All cases had a well-positioned ST-AMG at 1week and 75% (n= 9) had partial graft dissolution at 3weeks. Complete epithelialization without wound dehiscence was noted in all cases. However, secondary (after additional tumor treatment) symblepharon formed in 16.7% (n= 2). In all cases, the mean visual acuity and intraocular pressures remained unchanged during conjunctival reconstruction and subsequent secondary treatments. Post epithelialization adjuvant topical chemotherapy was given to extend treatment margins and treat presumed occult disease in 50% (n= 6). At mean follow-up of 25.5months (median 10, range 3-90), 10 cases (83.3%) showed complete local tumor control, 1 showed revascularization of the scleral melt, and 1 required orbital exenteration. ST-AMGs were easy to suture and relatively persistent. Epithelialization of the ocular surface without primary symblepharon formation was noted. ST-AMGs should be considered an alternative for ocular surface reconstruction.

Boron neutron capture therapy for vulvar melanoma and genital extramammary Paget\u2019s disease with curative responses

BackgroundAlthough the most commonly recommended treatment for melanoma and extramammary Paget’s disease (EMPD) of the genital region is wide surgical excision of the lesion, the procedure is highly invasive and can lead to functional and sexual problems. Alternative treatments have been used for local control when wide local excision was not feasible. Here, we describe four patients with genital malignancies who were treated with boron neutron capture therapy (BNCT).MethodsThe four patients included one patient with vulvar melanoma (VM) and three with genital EMPD. They underwent BNCT at the Kyoto University Research Reactor between 2005 and 2014 using para-boronophenylalanine as the boron delivery agent. They were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin/mucosal doses.ResultsAll patients showed similar tumor and normal tissue responses following BNCT and achieved complete responses within 6 months. The most severe normal tissue response was moderate skin erosion during the first 2 months, which diminished gradually thereafter. Dysuria or contact pain persisted for 2 months and resolved completely by 4 months.ConclusionsTreating VM and EMPD with BNCT resulted in complete local tumor control. Based on our clinical experience, we conclude that BNCT is a promising treatment for primary VM and EMPD of the genital region.Trial registration numbers UMIN000005124

Comparison of intrafascial and non-intrafascial radical prostatectomy for low risk localized prostate cancer

In this meta-analysis study, we compared the oncological and functional outcomes of intrafascial radical prostatectomy (IFRP) with non-intrafascial radical prostatectomy (NIFRP) in the treatment of patients with low risk localized prostate cancer (PCa). Relevant articles were identified by searching PubMed, EMBASE, Cochrane Library, Ovid, and the ISI Web of Knowledge databases. A total of 2096 patients were included from 7 eligible studies. Results of the pooled data showed that the oncological outcomes including gleason score, positive surgical margin and biochemical free survival rates were similar between the two groups. IFRP was superior to NIFRP with lower postoperative complication rates (RR 0.57, 95% CI 0.38, 0.85, p = 0.006), higher continence rates at 3 months post-operation (RR: 1.14; 95% CI, 1.04, 1.26; p = 0.006), and higher potency rates at 6 months (RR: 1.53; 95% CI, 1.07, 2.18; p = 0.02) and 12 months post-operation (RR: 1.38; 95% CI, 1.11, 1.73; p = 0.005). Additionally, there was a tendency towards higher potency rate in patients ≤65 years old compared with patients >65 years old after IFRP. Overall, these findings suggest that IFRP in young patients with low risk localized PCa had less postoperative complications, shortened time to return to continence and improved potency rate without compromising complete tumor control.

Cryoablation of Bone Metastases from Renal Cell Carcinoma for Local Tumor Control.

Patients with bone metastases from renal cell carcinoma often are not surgical candidates and have a poor prognosis. There are limited data on the use of cryoablation as a locoregional therapy for bone metastases. Our objective was to assess the local tumor-control rate following cryoablation of bone metastases in the setting of renal cell carcinoma. We retrospectively reviewed the medical records of patients with metastatic renal cell carcinoma who underwent cryoablation for bone metastases between 2007 and 2014. We excluded patients if the intent of treatment was for pain palliation only, if cryoablation was performed without an attempt for complete tumor control (cytoreduction), or if the patient had no further follow-up beyond the cryoablation procedure. We recorded patient demographics, procedural variables, and complications. Cross-sectional imaging and clinical follow-up were reviewed to determine disease recurrence. The median overall survival and recurrence-free survival were determined using the Kaplan-Meier method. Forty patients (30 male and 10 female) with 50 bone metastases were included for analysis. The mean patient age was 62 years (range, 47 to 82 years). The median follow-up was 35 months (95% confidence interval [CI], 22.7 to 74.4 months). Twenty-five (62.5%) of the 40 patients had oligometastatic disease, defined as ≤5 metastases at the time of ablation. The mean tumor size was 3.4 ± 1.5 cm. Metastases in the pelvic region represented 68% of the treated tumors (34 of 50). The overall local tumor-control rate per lesion was 82% (41 of 50). Patients with oligometastatic disease experienced better local tumor control (96% [24 of 25]) compared with patients who had >5 metastases (53.3% [8 of 15]) (p = 0.001). The local tumor-control rate was better for lesions for which a larger mean difference between maximum ice-ball diameter and maximum lesion diameter was achieved (2.2 ± 0.9 cm for those without recurrence versus 1.35 ± 1.2 cm for those with recurrence; p = 0.005). There were 3 grade-3 complications and 1 grade-4 complication. Cryoablation can be effective for achieving local oncologic control in bone metastases from renal cell carcinoma and may represent a valuable alternative to surgical metastasectomy in select patients. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Parafoveolar retinoblastoma regression with foveal preservation following intra-arterial chemotherapy documented on hand-held optical coherence tomography in a newborn

BackgroundOptical coherence tomography (OCT) has become an invaluable tool in retinoblastoma management, providing submillimeter visualization of tumor control following treatment. Herein, we document OCT-detection of a subtle tumor recurrence, allowing early intervention and achieving foveal microanatomy preservation.Case presentationA 3-week-old girl was diagnosed with bilateral familial retinoblastoma, classified as group D in the right eye (OD) and group B in the left eye (OS), and treated with intravenous chemoreduction. At 6-months follow-up, the right eye was under control, but the left eye revealed a subtle juxtafoveal tumor recurrence, documented on handheld OCT (HH-OCT) and measuring 2750 µm in diameter and 792 µm in thickness. Treatment with intraarterial chemotherapy (IAC) using 1 cycle of melphalan 5 mg was performed and complete tumor control was achieved, leaving a flat, concave scar 663 µm from the intact foveola and measuring 2750 µm in diameter and 120 µm in thickness. Foveal microanatomy OS was preserved on HH-OCT. The findings remained stable at 2 years following IAC.ConclusionsHH-OCT is an important tool in retinoblastoma management. In this case, HH-OCT allowed for early detection of retinoblastoma recurrence, before foveal invasion. Following treatment with IAC, complete tumor regression was noted and foveal microanatomy remained intact.

Efficacy of Iodine-125 Seed Implantation in Locoregionally Recurrent and Unresectable Breast Cancer: a Retrospective Study

The management of locoregionally recurrent and unresectable breast cancer is a therapeutic challenge. This retrospective study aimed to assess the efficacy of 125I seed implantation brachytherapy as a palliative management in locoregionally recurrent breast cancer. We analyzed 36 locoregionally recurrent and unresectable breast cancers in our hospital between 2012 and 2016. All patients were treated with CT-guided 125I seed permanent implantation. The dose distribution of 125I seeds was calculated using a computerized treatment planning system. Complete response, partial response, stable disease, and local tumor control rates were calculated. Long-term efficacy was assessed based on survival rates ranging from 1 to 4 years. The follow-up period ranged from 6 to 53 months. The median local control was 28 months (95% CI: 16.2–39.8 months). The percentage of patients who showed 6-month, 1-year, 2-year, and 3-year local control was 97.2%, 77.8%, 52.8%, and 33.3%, respectively. Median survival time for all patients was 48 months (95% CI: 40.9–55.1 months); 1-year, 2-year, 3-year, and 4-year survival rates were 97.2%, 80.6%, 63.9%, and 46.5%, respectively. Pain relief response rate was 88.9%. No serious complications were detected during the follow-up period. The results of this study demonstrate that 125I seed implantation could be considered a feasible and promising minimally invasive therapy for locoregionally recurrent and unresectable breast carcinoma.

Segmental Yttrium-90 Radioembolization versus Segmental Chemoembolization for Localized Hepatocellular Carcinoma: Results of a Single-Center, Retrospective, Propensity Score–Matched Study

PurposeTo compare segmental radioembolization with segmental chemoembolization for localized, unresectable hepatocellular carcinoma (HCC) not amenable to ablation. Materials and MethodsIn a single-center, retrospective study (2010–2015), 101 patients with 132 tumors underwent segmental radioembolization, and 77 patients with 103 tumors underwent segmental doxorubicin-based drug-eluting embolic or conventional chemoembolization. Patients receiving chemoembolization had worse performance status (Eastern Cooperative Oncology Group 0, 76% vs 56%; P = .003) and Child-Pugh class (class A, 65% vs 52%; P = .053); patients receiving radioembolization had larger tumors (32 mm vs 26 mm; P < .001), more infiltrative tumors (23% vs 9%; P = .01), and more vascular invasion (18% vs 1%; P < .001). Toxicity, tumor response, tumor progression, and survival were compared. Analyses were weighted using a propensity score (PS). ResultsToxicity rates were low, without significant differences. Index and overall complete response rates were 92% and 84% for radioembolization and 74% and 58% for chemoembolization (P = .001 and P < .001). Index tumor progression at 1 and 2 years was 8% and 15% in the radioembolization group and 30% and 42% in the chemoembolization group (P < .001). Median progression-free and overall survival were 564 days and 1,198 days in the radioembolization group and 271 days and 1,043 days in the chemoembolization group (PS-adjusted P = .002 and P = .35; censored by transplant PS-adjusted P < .001 and P = .064). ConclusionsSegmental radioembolization demonstrates higher complete response rates and local tumor control compared with segmental chemoembolization for HCC, with similar toxicity profiles. Superior progression-free survival was achieved.

A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin‐mediated Photodynamic Therapy

This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [1 O2 ]rx , to predict local control rate (LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma (RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm-2 ) and in-air fluence rates (50-150 mW cm-2 ) at Photofrin dosages of 5 and 15 mg kg-1 and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [1 O2 ]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [1 O2 ]rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [1 O2 ]rx ≥ 1.1 mm or PDT dose ≥1200 μm J cm-2 but cannot be predicted with fluence alone. LCR increases with increasing [1 O2 ]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [1 O2 ]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR.

Outcomes of Transarterial Chemoembolization With or Without Additional Radiofrequency Ablation in Hepatocellular Carcinoma of 2 to 5 cm in Diameter

Background: Hepatocellular carcinoma (HCC) is worldwide one of the most common and lethal malignant tumors despite at- tempts at treatment using various therapeutic modalities. Combination of transarterial chemoembolization (TACE) and radiofre- quency ablation (RFA) can have expanded indication as curative therapy in patients with larger size HCC (2 - 5 cm) that is unsuitable for RFA alone, but there are few studies showing long-term survival and larger sample size. Objectives: The goal of this study was to evaluate the long-term ecacy and safety of combined TACE with RFA, and TACE alone in hepatocellular carcinoma of 2 to 5 cm. Patients and Methods: This was a retrospective study including 207 consecutive patients who were enrolled using computerized hepatocellular carcinoma database consisting of 105 patients who underwent combined TACE with RFA, and 102 patients who un- derwent TACE alone with long-term follow-up. Results: The complete remission rate was meaningfully higher in the combination group (97.1%, 102/105) than in the TACE group (54.9%, 56/102) (P < 0.001). The mean follow-up periods of the combination group and the TACE group were 49.3 16.9 months and 46.3 26.7 months, respectively. The TACE group (90.2%, 92/102) showed significantly higher tumoral recurrence or persistence than the combination group (59.0%, 62/105) during follow-up periods (P < 0.001). The cumulative survival rates at 1, 2, 3, 4, and 5 years were 88.6, 82.9, 79.0, 75.2, and 74.3%, respectively in the combination group and 93.1, 73.5, 59.8, 50.0, and 45.1%, respectively in the TACE group. Independent factors associated with improved overall survival were the combination group, Child-Pugh class A, complete remission at 1 month, negative intrahepatic new tumors, and no adverse event. Conclusions: Complete local tumor control by combination of TACE with RFA could improve overall survival in comparison with TACE alone for long-term follow-up. The combination of TACE with RFA should be considered for achieving complete local tumor control before progression to advanced stage in HCC of 2 to 5 cm.

Repeated iodine-125 seed implantations combined with external beam radiotherapy for the treatment of locally recurrent or metastatic stage III/IV non-small cell lung cancer: a retrospective study.

BackgroundRecurrent or metastatic lung cancer is difficult to manage. This retrospective study aimed to assess the efficacy of repeated iodine-125 seed implantations combined with external beam radiotherapy (EBRT) for locally recurrent or metastatic stage-III/IV non-small cell lung cancer (NSCLC).MethodsEighteen previously treated stage-III/IV NSCLC patients with local or metastatic recurrences underwent 1-to-3 iodine-125 implantations. Six of these patients received palliative EBRT and six patients received combined chemotherapy using gemcitabine and cisplatin. Near-term treatment efficacy was evaluated 3 months after seed implantation by comparing changes in tumor size on computed tomography images; the evaluated outcomes were complete response, partial response, stable disease, and local tumor control rate. Long-term efficacy was assessed based on 1- and 2-year survival rates.ResultsPatients were followed up for 6 to 50 months. The overall (i.e., complete + partial) response rate was 87.4 %. The local control rates after the first, second, and third years were 94.1, 58.8 and 41.2 %, respectively.ConclusionsThe results of this study demonstrated that repeated implantation of radioactive particles combined with EBRT is a safe treatment that effectively controlled local recurrence and metastasis of stage III/IV NSCLC.

Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes

Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control.

Plasma ceramide, a real-time predictive marker of pulmonary and hepatic metastases response to stereotactic body radiation therapy combined with irinotecan

Background and purposesEarly biomarkers of tumour response are needed to discriminate between responders and non-responders to radiotherapy. We evaluated the ability of ceramide, a bioactive sphingolipid, to predict tumour sensitivity in patients treated by hypofractionated stereotactic body radiation therapy (SBRT) combined with irinotecan chemotherapy. Materials and methodsPlasma levels of total ceramide and of its subspecies were measured before and during treatment in 35 patients with liver and lung oligometastases of colorectal cancer included in a phase II trial. Cer levels were quantified by LC–ESI-MS/MS and compared to tumour volume response evaluated one year later by CT-scan. ResultsPretreatment plasma ceramide levels were not indicative of tumour response. Nevertheless, the levels of total ceramide and of its 4 main subspecies were significantly higher at days 3 and 10 of treatment in objective responders than in non-responders. According to Kaplan–Meier curves, almost complete tumour control was achieved at 1year in patients with increased total ceramide levels whereas 50% of patients with decreased levels experienced an increase in tumour volume. ConclusionsTotal plasma ceramide is a promising biomarker of tumour response to SBRT combined with irinotecan that should enable to segregate patients with high risk of tumour escape.

Complete local tumor control after curettage of chondroblastoma–a retrospective analysis

BackgroundChondroblastoma is an uncommon benign bone tumor with an incidence of 1 to 2% among all primary bone tumors. In the past, treatment for chondroblastoma has been highly variable leading to different rates of recurrences. Therefore we aimed to determine: (1) the rate of recurrence, (2) the complication rate, (3) and functional outcome after intralesional curettage of chondroblastoma. HypothesesIntralesional curettage with high speed burring and packing can avoid local recurrences. Patients and methodsExperiences of 22 patients with chondroblastoma of the bone were retrospectively reviewed. The patient group consisted of 16 men; 6 women; mean age 24years (range; 12–58years) affecting in 15 the lower- (68%) and in seven the upper extremity (32%). ResultsThere was no local recurrence or malignant transformation. All patients underwent intralesional curettage, followed by defect filling presenting in 19 patients (87%) excellent clinical and oncological results (mean MSTS 98.9). Complications were seen in two patients. Pain was the main revealing symptom of the chondroblastoma (n=16, 73%). Mean follow-up of all patients was 114months (range, 25 to 480months). DiscussionAggressive curettage and packing provided excellent local tumor control and functional results in our patients with chondroblastoma. Malignant transformation is extremely rare, however, present in literature but was not seen in any of our patients. Level of evidenceLevel IV, retrospective study.