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The cure rate for metastatic or relapsed osteosarcoma has not substantially improved over the past decades despite the exploitation of multimodal treatment approaches, allowing long-term survival in less than 30% of cases. Patients with osteosarcoma often develop resistance to chemotherapeutic agents, where personalized targeted therapies should offer new hope. T cell immunotherapy as a complementary or alternative treatment modality is advancing rapidly in general, but its potential against osteosarcoma remains largely unexplored. Strategies incorporating immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) modified T cells, and T cell engaging bispecific antibodies (BsAbs) are being explored to tackle relapsed or refractory osteosarcoma. However, osteosarcoma is an inherently heterogeneous tumor, both at the intra- and inter-tumor level, with no identical driver mutations. It has a pro-tumoral microenvironment, where bone cells, stromal cells, neovasculature, suppressive immune cells, and a mineralized extracellular matrix (ECM) combine to derail T cell infiltration and its anti-tumor function. To realize the potential of T cell immunotherapy in osteosarcoma, an integrated approach targeting this complex ecosystem needs smart planning and execution. Herein, we review the current status of T cell immunotherapies for osteosarcoma, summarize the challenges encountered, and explore combination strategies to overcome these hurdles, with the ultimate goal of curing osteosarcoma with less acute and long-term side effects. [ABSTRACT FROM AUTHOR]

A cardinal feature that distinguishes clinically high-risk neuroblastoma from low-risk tumors is telomere maintenance. Specifically, neuroblastoma tumors with either active telomerase or alternative lengthening of telomeres exhibit aggressive growth characteristics that lead to poor outcomes, whereas tumors without telomere maintenance can be managed with observation or minimal treatment. Even though the need for cancer cells to maintain telomere DNA—in order to sustain cell proliferation—is well established, recent studies suggest that the neural crest origin of neuroblastoma may enforce unique relationships between telomeres and tumor malignancy. Specifically in neuroblastoma, telomere structure and telomerase activity are correlated with the adrenergic/mesenchymal differentiation states, and manipulating telomerase activity can trigger tumor cell differentiation. Both findings may reflect features of normal neural crest development. This review summarizes recent advances in the characterization of telomere structure and telomere maintenance mechanisms in neuroblastoma and discusses the findings in the context of relevant literature on telomeres during embryonic and neural development. Understanding the canonical and non-canonical roles of telomere maintenance in neuroblastoma could reveal vulnerabilities for telomere-directed therapies with potential applications to other pediatric malignancies. [ABSTRACT FROM AUTHOR]

To examine the feasibility of using a mobile phone app to remotely monitor patient-reported outcomes (PROs) during and immediately after radiation therapy (RT) for breast and prostate cancer. English-speaking patients receiving RT for breast or prostate cancer were invited to participate in a single-center, longitudinal quality improvement project. Participants were asked to download a HIPAA/PHIPA compliant mobile phone app onto their personal device. Unsupervised participants used the app to report PRO-CTCAE at baseline, weekly during RT and up to 4 weeks after RT. Push notifications automatically delivered reminders to complete surveys. Participants were routinely seen by a radiation healthcare provider (HCP) once per week during RT. PROs were remotely monitored by Radiation Therapists during and after RT, with an intervention threshold of 'moderate' or greater symptom severity. The app also collected pre and post patient-centered communication data (PCC-Ca-6), and participant satisfaction. App use metrics were gathered from audit log timestamps (open and interacting). From July 2023 to Feb 2024, 20 prostate and 20 breast cancer patients participated (31% of the eligible population). The mean completion rate for all PRO surveys across all time points was 75%. Mean age was 64 (SD 14; range = 25-93) years, 50% were female, and 83% preferred to communicate in English. There were no statistically significant demographic differences between those who were: 1) enrolled and compliant (> 70% survey completion); 2) enrolled but poorly compliant (<70% completion); and 3) approached but chose not to participate (p > 0.7). During RT, PRO-CTCAE was reported 85 times (out of a possible 107), whereas HCPs documented 49 times using various quantitative scales (e.g. RTOG, ESAS). In the 'post-RT' period, PRO entries triggered early follow-up with 8 breast and 10 prostate patients. There were no significant differences between pre and post overall PCC-Ca-6 scores (mean: 110 vs. 108; p 0.35). On average, each patient logged into the app 16 times on 11 days. They spent an average of 7 minutes interacting with the app per session. At the end of the study, 65% of participants said they would recommend using the app to other RT patients. 7 participants voluntarily populated their personal app account with unsolicited details (e.g. other health conditions and symptoms). These preliminary results suggest that remote monitoring of PROs entered via a mobile app is feasible during and immediately after RT. It is minimally burdensome to patients across a broad range of demographics and has no impact on their perceptions of patient-centered communication. A randomized controlled trial will now evaluate the use of remote PRO monitoring to triage attendance at in-person Oncologist review visits to identify the efficacy of a PRO-based personalized approach to providing supportive care. [ABSTRACT FROM AUTHOR]

Immunotherapy has emerged as an attractive option for patients with relapsed or refractory high-risk neuroblastoma (HRNB). Neuroblastoma (NB), a sympathetic nervous system cancer arising from an embryonic neural crest cell, is heterogeneous clinically, with outcomes ranging from an isolated abdominal mass that spontaneously regresses to a widely metastatic disease with cure rates of about 50% despite intensive multimodal treatment. Risk group stratification and stage-adapted therapy to achieve cure with minimal toxicities have accomplished major milestones. Targeted immunotherapeutic approaches including monoclonal antibodies, vaccines, adoptive cellular therapies, their combinations, and their integration into standard of care are attractive therapeutic options, although curative challenges and toxicity concerns remain. In this review, we provide an overview of immune approaches to NB and the tumor microenvironment (TME) within the clinical translational framework. We propose a novel T cell-based therapeutic approach that leverages the unique properties of tumor surface antigens such as ganglioside GD2, incorporating specific monoclonal antibodies and recent advancements in adoptive cell therapy. [ABSTRACT FROM AUTHOR]

Technological advancement has facilitated patient-specific radiotherapy in bladder cancer. This has been made possible by developments in image-guided radiotherapy (IGRT). Particularly transformative has been the integration of volumetric imaging into the workflow. The ability to visualise the bladder target using cone beam computed tomography and magnetic resonance imaging initially assisted with determining the magnitude of inter- and intra-fraction target change. It has led to greater confidence in ascertaining true anatomy at each fraction. The increased certainty of dose delivered to the bladder has permitted the safe reduction of planning target volume margins. IGRT has therefore improved target coverage with a reduction in integral dose to the surrounding tissue. Use of IGRT to feed back into plan and dose delivery optimisation according to the anatomy of the day has enabled adaptive radiotherapy bladder solutions. Here we undertake a review of the stepwise developments underpinning IGRT and adaptive radiotherapy strategies for external beam bladder cancer radiotherapy. We present the evidence in accordance with the framework for systematic clinical evaluation of technical innovations in radiation oncology (R-IDEAL). [ABSTRACT FROM AUTHOR]

Background: The cure rate for metastatic osteosarcoma has not substantially improved over the past decades. Clinical trials of anti-HER2 trastuzumab or anti-GD2 dinutuximab for metastatic or refractory osteosarcoma were not successful, and neither was immune checkpoint inhibitors (ICIs). Methods: We tested various target antigen expressions on osteosarcoma cell lines using flow cytometry and analyzed in vitro T cell engaging BsAb (T-BsAb)-dependent T cell-mediated cytotoxicity using 4-h 51Cr release assay. We tested in vivo anti-tumor activities of T-BsAb targeting GD2 or HER2 in established osteosarcoma cell line or patient-derived xenograft (PDX) mouse models carried out in BALB-Rag2−/−IL-2R-γc-KO (BRG) mice. We also generated ex vivo BsAb-armed T cells (EATs) and studied their tumor-suppressive effect against osteosarcoma xenografts. In order to improve the anti-tumor response, ICIs, anti-human PD-1 (pembrolizumab) or anti-human PD-L1 (atezolizumab) antibodies were tested their synergy with GD2- or HER2-BsAb against osteosarcoma. Results: GD2 and HER2 were chosen from a panel of surface markers on osteosarcoma cell lines and PDXs. Anti-GD2 BsAb or anti-HER2 BsAb exerted potent anti-tumor effect against osteosarcoma tumors in vitro and in vivo. T cells armed with anti-GD2-BsAb (GD2-EATs) or anti-HER2-BsAb (HER2-EATs) showed significant anti-tumor activities as well. Anti-PD-L1 combination treatment enhanced BsAb-armed T cell function in vivo and improved tumor control and survival of the mice, when given sequentially and continuously. Conclusion: Anti-GD2 and anti-HER2 BsAbs were effective in controlling osteosarcoma. These data support the clinical investigation of GD2 and HER2 targeted T-BsAb treatment in combination with immune checkpoint inhibitors, particularly anti-PD-L1, in patients with osteosarcoma to improve their treatment outcome. [ABSTRACT FROM AUTHOR]

Early warning systems have often been considered an effective risk mitigation tools for landslides. In 1977, the Geotechnical Engineering Office (GEO) of Hong Kong government established the world's first territorial-wide early warning system for landslide disaster. The Landslip Warning System (LWS) has then been continuously enhanced and upgraded in response to the enrichment of rainfall and landslide database, advancement in instrumentation techniques and change in public perception of landslide risk over the last 40 years. This article consolidates the extensive experience of Hong Kong in using the landslip early warning system (LEWS) as a landslide risk management tool. A comprehensive review on the development process of the rainfall-landslide prediction models is presented. The landslide prediction model evolved from a rainfall duration-intensity model (late 1970) to a simple rainfall threshold model (middle 1980 to late 1990), then to a rainfall-landslide density model (early 2000) and rainfall-landslide frequency model (middle 2000s onward). Through regular review and update of the prediction model taking into account the availability of more recent data and activities that alter landslide risks, the performance of prediction model could be enhanced. The number of rain gauges expanded from 20 to 92 to support the operation of different generations of LWS. The GEO is currently adopting internet of thing (IOT) and cloud computing technology to enhance the resilience of the LWS, especially during extreme weather condition. [ABSTRACT FROM AUTHOR]

Introduction: This study is a five-year follow-up of previously published review of the trauma workload at our institution. It aims to provide evidence about the quality of trauma care delivered by a major academic trauma service in South Africa to provide a temporal analysis of trauma trends in the city of Pietermaritzburg.Materials and methods: All trauma patients admitted by the Pietermaritzburg Metropolitan Trauma Service (PMTS) for the period December 2012-April 2018 were retrieved from the Hybrid Electronic Medical Registry (HEMR) for analysis.Results: Over the five-year period, a total of 8722 trauma patients were admitted to Grey's Hospital. There were 7242 (83.0%) males. The average age was 29.66 years. A total of 1719 (19.7%) patients less than 19 years of age, 377 (4.3%) older than 60 years of age and 1480 (17.0%) female patients were admitted following trauma. Table 3 breaks down the mechanism of trauma. A total of 5027 patients sustained blunt trauma (57.6%), and 3334 (38.5%) sustained penetrating trauma. A total of 4808 patients sustained intentional trauma implying that 55.1% of all trauma was secondary to grievous bodily harm or assault either in the form of a stab wound or GSW or of an assault. There was a total of 2232 road traffic-related incidents, of which 37.9% (845) were pedestrian victims. The mortality rate for all trauma admissions was 4.5% (396). Of these 396 deaths, 64 (16.2%) were classified at the morbidity and mortality conference as being avoidable.Conclusions: The HEMR has allowed us to track the burden of trauma presenting to our institution over a five-year period. This confirms previous studies over shorter time periods from our institution. The pattern of trauma has remained consistent, and the previously described high levels show no sign of decreasing. Interventions to try and reduce this burden are urgently required. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to review the trauma workload and operative exposure in a major South African trauma center and provide a comparison with contemporary experience from major military conflict. Materials and methods: All patients admitted to the PMTS following trauma were identified from the HEMR. Basic demographic data including mechanism of injury and body region injured were reviewed. All operative procedures were categorized. The total operative volume was compared with those available from contemporary literature documenting experience from military conflict in Afghanistan. Operative volume was converted to number of cases per year for comparison. Results: During the 4-year study period, 11,548 patients were admitted to our trauma center. Eighty-four percent were male and the mean age was 29 years. There were 4974 cases of penetrating trauma, of which 3820 (77%) were stab wounds (SWs), 1006 (20%) gunshot wounds (GSWs) and the remaining 148 (3%) were animal injuries. There were 6574 cases of blunt trauma. The mechanism of injuries was as follows: assaults 2956, road traffic accidents 2674, falls 664, hangings 67, animal injuries 42, sports injury 29 and other injuries 142. A total of 4207 operations were performed. The volumes per year were equivalent to those reported from the military surgical literature. Conclusion: South Africa has sufficient burden of trauma to train combat surgeons. Each index case as identified from the military surgery literature has a sufficient volume in our center. Based on our work load, a 6-month rotation should be sufficient to provide exposure to almost all the major traumatic conditions likely to be encountered on the modern battlefield. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling. Bispecific antibodies (BsAb) combine the binding specificities of two different monoclonal antibodies, one activating a receptor on a killer effector cell, while the other engaging a tumor-associated antigen to initiate tumor cytotoxicity. In this review, we survey the HCC targets for which CARs and bispecific antibodies have been generated. The pros and cons of these targets for T-cell and Natural Killer cell based immunotherapy will be discussed. [ABSTRACT FROM AUTHOR]

Bispecific antibodies (BsAb) are a new generation of antibody-based therapy, conveying artificial specificity to polyclonal T cells or radiohaptens. These drugs have been successfully implemented to cure hematologic malignancies and are under clinical investigation for solid tumors including HRNB. BsAbs designed to engage T cells or increase the therapeutic index of radiotherapy hold the potential to significantly improve the long-term survival of HRNB patients by shrinking bulky tumors and more effectively eliminating micrometastases and preventing relapse. BsAbs can also be used to arm T cells, yielding a product analogous to CAR T cells, possibly with an improved safety profile. A thoughtful and realistic integration of these therapies into the standard of care should benefit more patients worldwide. Here we describe the history of development of BsAbs for HRNB, which dates back almost three decades. We discuss the merits and pitfalls of all relevant BsAbs, including T cell-engagers and agents used for radioimmunotherapy, highlighting the importance of structural design and interdomain spacing for anti-tumor efficacy. [ABSTRACT FROM AUTHOR]

The article emphasizes the importance of discussing with patients the risks associated with the peri-operative surgical process. Topics discussed include the mortality risk relating to the induction of anesthesia, importance of harm and benefit perception to health decision making, need of pre-operative testing to reduce peri-operative risk, key objective of peri-operative risk assessment, and risk associated with peri-operative pharmacological interventions.

Abstract: Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and sarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma in children and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas in adults. Since GD2 expression in normal tissues is restricted to the brain, which is inaccessible to circulating antibodies, and in selected peripheral nerves and melanocytes, it was deemed a suitable target for systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested in clinical trials for neuroblastoma for over the past two decades, with proven safety and efficacy. The main limitations have been acute pain toxicity associated with GD2 expression on peripheral nerve fibers and the inability of antibodies to treat bulky tumor. Several strategies have been developed to reduce pain toxicity, including bypassing complement activation, using blocking antibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on peripheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal antibodies and fragments have been engineered into immunocytokines, immunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted nanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen receptors. The challenges of these approaches will be reviewed to build a perspective for next generation anti-GD2 therapeutics in cancer therapy. [Copyright &y& Elsevier]

Neuroblastoma is a solid tumour that arises from the developing sympathetic nervous system. Over the past decade, our understanding of this disease has advanced tremendously. The future challenge is to apply the knowledge gained to developing risk-based therapies and, ultimately, improving outcome. In this Review we discuss the key discoveries in the developmental biology, molecular genetics and immunology of neuroblastoma, as well as new translational tools for bringing these promising scientific advances into the clinic. [ABSTRACT FROM AUTHOR]

Murine IgG3 anti-GD2 antibody m3F8 has shown anti-neuroblastoma activity in Phase I/II studies, where antibody-dependent cell-mediated cytotoxicity (ADCC) played a key role. Humanization of m3F8 should circumvent human anti-mouse antibody (HAMA) response and enhance its ADCC properties to reduce dosing and pain side effect. Chimeric 3F8 (ch3F8) and humanized 3F8 (hu3F8-IgG1 and hu3F8-IgG4) were produced and purified by protein A affinity chromatography. In vitro comparison was made with m3F8 and other anti-GD2 antibodies in binding, cytotoxicity, and cross-reactivity assays. In GD2 binding studies by SPR, ch3F8 and hu3F8 maintained KD comparable to m3F8. Unlike other anti-GD2 antibodies, m3F8, ch3F8 and hu3F8 had substantially slower koff.. Similar to m3F8, both ch3F8 and hu3F8 inhibited tumor cell growth in vitro, while cross-reactivity with other gangliosides was comparable to that of m3F8. Both peripheral blood mononuclear cell (PBMC)-ADCC and polymorphonuclear leukocytes (PMN)-ADCC of ch3F8 and hu3F8-IgG1 were more potent than m3F8. This superiority was consistently observed in ADCC assays, irrespective of donors or NK-92MI-transfected human CD16 or CD32, whereas complement mediated cytotoxicity (CMC) was reduced. As expected, hu3F8-IgG4 had near absent PBMC-ADCC and CMC. Hu3F8 and m3F8 had similar tumor-to-non tumor ratios in biodistribution studies. Anti-tumor effect against neuroblastoma xenografts was better with hu3F8-IgG1 than m3F8. In conclusion, humanizing m3F8 produced next generation anti-GD2 antibodies with substantially more potent ADCC in vitro and anti-tumor activity in vivo. By leveraging ADCC over CMC, they may be clinically more effective, while minimizing pain and HAMA side effects. A Phase I trial using hu3F8-IgG1 is ongoing. [ABSTRACT FROM AUTHOR]

The article discusses a study of the genetic mutations that are related to age at diagnosis in patients who have metastatic neuroblastoma (MN). The researchers examined the deoxyribonucleic acid from diagnostic tumors from 104 patients who have MN, collected between 1987 and 2009, using whole genome sequencing. They found somatic mutations in transcriptional regulator ATRX in 100 percent of tumors from patients in the adolescent and young adult group, in 17 percent of tumors from children, and zero percent of tumors from infants.

The BMI1 gene is overexpressed in -90% of human neuroblastomas. However, little is known about the regulation of BMI1 expression. Using microarray and immunohistochemical analysis, we show that BMI1 expression correlated with MYCN levels in MYCN-amplified human neuroblastomas, and with MYC levels in the MYCN-nonamplified group. We further demonstrated that BMI1 is a direct target gene of MYCN/MYC in 3 neuroblastoma cell lines: BE (2)-C, LAN1, and SH-SY5Y. Overexpression of MYCN or MYC transactivated the BMI1 promoter and up-regulated BMI1 gene expression, shRNA-mediated knockdown of MYCN or MYC decreased BMI1 gene expression. Chromatin immunoprecipitation and point-mutation assays revealed that both MYCN and MYC bind to the E-box within the BMI1 promoter. Overexpression of BMI1, MYCN, and MYC independently increased both cell proliferation and tumor growth. Conversely, specific inhibition of BMI1, MYCN, and MYC decreased tumor cell proliferation and tumor growth. Interestingly, BMI1 suppression in MYCN/ MYC-overexpressing cells resulted in significantly greater inhibition compared to that in mock-transduced and parental cells. Our results indicate that MYCN and MYC regulate BMI1 gene expression at the transcriptional level and that dysregulation of the BMI1 gene mediated by MYCN or MYC overexpression, confers increased cell proliferation during neuroblastoma genesis and tumor progression. [ABSTRACT FROM AUTHOR]

Purpose: To present a large experience (73 patients) using a standard radiotherapy (RT) protocol to prevent relapse in cranial sites where measurable metastatic neuroblastoma (NB), an adverse prognostic marker, is common. Methods and Materials: High-risk NB patients with measurable cranial disease at diagnosis or residual cranial disease after induction therapy had those sites irradiated with hyperfractionated 21 Gy; a brain-sparing technique was used for an extensive field. The patients were grouped according to the response to systemic therapy. Thus, when irradiated, Group 1 patients were in complete remission and Group 2 patients had primary refractory disease. Follow-up was from the start of cranial RT. Results: At 3 years, the 39 Group 1 patients had a progression-free survival rate of 51%; control of cranial disease was 79%. Two relapses involved irradiated cranial sites. Two other patients relapsed in the irradiated cranial sites 6 and 12 months after a systemic relapse. At 3 years, the 34 Group 2 patients had a progression-free survival rate of 33%; control of cranial disease was 52%. Group 2 included 19 patients who had residual cranial (with or without extracranial) disease. The cranial sites showed major (n = 13), minor (n = 2), or no response (n = 4) to RT. Five patients had progression in the cranial RT field at 10–27 months. Group 2 also included 15 patients who had persistent NB in extracranial, but not cranial, sites. Of these 15 patients, 2 relapsed in the irradiated cranial sites and elsewhere at 8 and 14 months. Cranial RT was well tolerated, with no Grade 2 or greater toxicity. Conclusion: Hyperfractionated 21-Gy cranial RT might help control NB and is feasible without significant toxicity in children. [Copyright &y& Elsevier]

Background: Neuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. Clinical distinction of stage 4s from lethal stage 4 can be difficult, but critical for therapeutic decisions. The aim of this study was to investigate chromosomal alterations and differential gene expression amongst infant disseminated NB subgroups. Methods: Thirty-five NB tumours from patients diagnosed at < 18 months (25 stage 4 and 10 stage 4s), were evaluated by allelic and gene expression analyses. Results: All stage 4s patients underwent spontaneous remission, only 48% stage 4 patients survived despite combined modality therapy. Stage 4 tumours were 90% near-diploid/tetraploid, 44% MYCN amplified, 77% had 1p LOH (50% 1p36), 23% 11q and/or 14q LOH (27%) and 47% had 17q gain. Stage 4s were 90% near-triploid, none MYCN amplified and LOH was restricted to 11q. Initial comparison analyses between stage 4s and 4 < 12 months tumours revealed distinct gene expression profiles. A significant portion of genes mapped to chromosome 1 (P < 0.0001), 90% with higher expression in stage 4s, and chromosome 11 (P = 0.0054), 91% with higher expression in stage 4. Less definite expression profiles were observed between stage 4s and 4 < 18m, yet, association with chromosomes 1 (P < 0.0001) and 11 (P = 0.005) was maintained. Distinct gene expression profiles but no significant association with specific chromosomal region localization was observed between stage 4s and stage 4 < 18 months without MYCN amplification. Conclusion: Specific chromosomal aberrations are associated with distinct gene expression profiles which characterize spontaneously regressing or aggressive infant NB, providing the biological basis for the distinct clinical behaviour. [ABSTRACT FROM AUTHOR]

Gabapentin is a second generation anticonvulsant that is effective in the treatment of chronic neuropathic pain. It was not, until recently, thought to be useful in acute perioperative conditions. However, a growing body of evidence suggests that perioperative administration is efficacious for postoperative analgesia, preoperative anxiolysis, attenuation of the haemodynamic response to laryngoscopy and intubation, and preventing chronic post-surgical pain, postoperative nausea and vomiting, and delirium. This article reviews the clinical trial data describing the efficacy and safety of gabapentin in the setting of perioperative anaesthetic management. [ABSTRACT FROM AUTHOR]

Chimeric immune receptors (CIR) transduced into lymphocytes link target recognition by single chain antibody Fv (scFv) to activation through CD28/TCRζ signaling. As surrogate antigens, anti-idiotypic antibodies may facilitate gene-transduction and clonal expansion of human lymphocytes for in vivo tumor therapy. The murine monoclonal antibody (MAb) 8H9 reacts with a novel antigen widely expressed on solid tumors. A CIR consisting of human CD8-leader sequence, 8H9-scFv, CD28 (transmembrane and cytoplasmic domains), and TCR-ζ chain was constructed, ligated into the pMSCVneo vector, and used to transfect the packaging line GP + envAM12 bearing an amphotropic envelope. Rat anti-idiotypic MAb 2E9 (IgG2a) was used to clone retroviral producer line as well as to expand gene-modified primary human lymphocytes. Sequential enrichments using either affinity chromatography or cell sorting using anti-idiotypic MAb 2E9 significantly improved the percentage of producer clones positive for surface 8H9-scFv and the efficiency of their supernatant in transducing the indicator cell line K562. By 3 weeks of in vitro culture, >95% of transduced primary human lymphocytes were CIR-positive. Upon periodic stimulation with 2E9, these lymphocytes underwent >106-fold expansion by 6 months in culture. They mediated antigen-specific non-MHC restricted cytokine release and tumor cytotoxicity, and inhibited human xenograft engraftment in SCID mice. Anti-idiotypic antibody may provide a useful tool for optimizing gene transduction of CIR fusion constructs into primary human lymphocytes and their continual expansion in vitro. [ABSTRACT FROM AUTHOR]

Presents information on a study which investigated the detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors. Forms of treatment-related leukemia; Materials and methods of the study; Results and discussion.

The author reflects on neuroblastoma and on research which has been performed in an effort to find a genetic link to the disease. He suggests that there are challenges in trying to establish a meaningful association between common alleles and complex diseases. He argues that the rarity of neuroblastoma and several other factors rule out any value for genetic screening for the disease.

Poster: Clinical track: Prostate PO-1203: Urethral sparing prostate SABR with integrated boost: novel by-stander effect of hydrogel spacer A. Billfalk Kelly, V. Kong, P. Bettoli, J. Helou, P. Chung, A. Berlin. [Extracted from the article]

Presents a letter to the editor about bilateral rhegmatogenous retinal detachments that occur due to multiple round atrophic holes, published in the March 3, 2004 issue of the journal Eye.

Background: There is limited evidence to suggest that the more distal a penetrating colonic injury, the poorer its expected outcome, prompting consideration of diversion rather than anastomosis when faced with left colonic injury. The clinical outcomes of penetrating colonic trauma in relation to their anatomical location within the colon were reviewed. Methods: A review was performed over eight years (2012—2020) of all patients over 18 years who had sustained penetrating colon injury and presented to our trauma centre in South Africa. Direct comparison was made between right colon vs left colon injuries. Results: A total of 450 patients were included; right colon: 260, left colon: 190. Gunshots predominated in the right colon, and the PATI was higher in this group. There were minimal differences in admission physiology and blood gas parameters between groups, but higher damage control surgery and ICU admission rates for the right colon group. There were similar rates of primary repair, anastomosis, and stoma between groups. Leak rates were no different between the two groups, and although overall complication rates were higher for the right colon, there was no difference with regard to gastro-intestinal and other complications, nor for mortality. While regression analysis did identify PATI to be a risk factor for overall complications and mortality, it failed to do so for anastomotic leak. Conclusion: Our study did not demonstrate any difference in anastomotic leak rates or mortality between right vs left colonic injury. We recommend that all colonic injuries should be treated on their own merit, balanced against the patient's condition, regardless of anatomical location within the colon. [ABSTRACT FROM AUTHOR]

Background: Tumor microenvironment (TME) is a dynamic cellular milieu to promote tumor angiogenesis, growth, proliferation, and metastasis, while derailing the host anti-tumor response. TME impedes bispecific antibody (BsAb) or chimeric antigen receptor (CAR)-driven T cells infiltration, survival, and cytotoxic efficacy. Modulating tumor infiltrating myeloid cells (TIMs) could potentially improve the efficacy of BsAb. Methods: We evaluated the effects of TIM modulation on BsAb-driven T cell infiltration into tumors, their persistence, and in vivo anti-tumor response. Anti-GD2 BsAb and anti-HER2 BsAb built on IgG-[L]-scFv platform were tested against human cancer xenografts in BALB-Rag2-/-IL-2R-γc-KO (BRG) mice. Depleting antibodies specific for polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic MDSC (M-MDSC), and tumor associated macrophage (TAM) were used to study the role of each TIM component. Dexamethasone, an established anti-inflammatory agent, was tested for its effect on TIMs. Results: BsAb-driven T cells recruited myeloid cells into human tumor xenografts. Each TIM targeting therapy depleted cells of interest in blood and in tumors. Depletion of PMN-MDSCs, M-MDSCs, and particularly TAMs was associated with enhanced T cell infiltration into tumors, significantly improving tumor control and survival in multiple cancer xenograft models. Dexamethasone premedication depleted monocytes in circulation and TAMs in tumors, enhanced BsAb-driven T cell infiltration, and anti-tumor response with survival benefit. Conclusion: Reducing TIMs markedly enhanced anti-tumor effects of BsAb-based T cell immunotherapy by improving intratumoral T cell infiltration and persistence. TAM depletion was more effective than PMN- or M-MDSCs depletion at boosting the anti-tumor response of T cell engaging BsAb. [ABSTRACT FROM AUTHOR]

Background EGFR and/or HER2 expression in pancreatic cancers is correlated with poor prognoses. We generated homodimeric (EGFRxEGFR or HER2xHER2) and heterodimeric (EGFRxHER2) T cell-engaging bispecific antibodies (T-BsAbs) to direct polyclonal T cells to these antigens on pancreatic tumors. Methods EGFR and HER2 T-BsAbs were constructed using the 2+2 IgG-[L]-scFv T-BsAbs format bearing two anti-CD3 scFvs attached to the light chains of an IgG to engage T cells while retaining bivalent binding to tumor antigens with both Fab arms. A Fab arm exchange strategy was used to generate EGFRxHER2 heterodimeric T-BsAb carrying one Fab specific for EGFR and one for HER2. EGFR and HER2 T-BsAbs were also heterodimerized with a CD33 control T-BsAb to generate ‘tumor-monovalent’ EGFRxCD33 and HER2xCD33 T-BsAbs. T-BsAb avidity for tumor cells was studied by flow cytometry, cytotoxicity by T-cell mediated 51Chromium release, and in vivo efficacy against cell line-derived xenografts (CDX) or patient-derived xenografts (PDX). Tumor infiltration by T cells transduced with luciferase reporter was quantified by bioluminescence. Results The EGFRxEGFR, HER2xHER2, and EGFRxHER2 T-BsAbs demonstrated high avidity and T cell-mediated cytotoxicity against human pancreatic ductal adenocarcinoma (PDAC) cell lines in vitro with EC50s in the picomolar range (0.17pM to 18pM). They were highly efficient in driving human polyclonal T cells into subcutaneous PDAC xenografts and mediated potent T cell-mediated anti-tumor effects. Both EGFRxCD33 and HER2xCD33 tumormonovalent T-BsAbs displayed substantially reduced avidity by SPR when compared to homodimeric EGFRxEGFR or HER2xHER2 T-BsAbs (∼150-fold and ∼6000-fold respectively), tumor binding by FACS (8.0-fold and 63.6-fold), and T-cell mediated cytotoxicity (7.7-fold and 47.2-fold), while showing no efficacy against CDX or PDX. However, if either EGFR or HER2 was removed from SW1990 by CRISPR-mediated knockout, the in vivo efficacy of heterodimeric EGFRxHER2 T-BsAb was lost. Conclusion EGFR and HER2 were useful targets for driving T cell infiltration and tumor ablation. Two arm Fab binding to either one or both targets was critical for robust anti-tumor effect in vivo. By engaging both targets, EGFRxHER2 heterodimeric T-BsAb exhibited potent anti-tumor effects if CDX or PDX were EGFR+HER2+ double-positive with the potential to spare single-positive normal tissue. [ABSTRACT FROM AUTHOR]

Purpose: For patients with high-risk neuroblastoma (HR-NB), a dose of 21 Gy to the primary tumor site after gross total resection (GTR) provides excellent local control. However, no clinical trial has specifically evaluated the optimal dose of radiation therapy (RT), and RT-related long-term toxicities are of increasing concern. We sought to assess local control, survival outcomes, and toxicity after a reduction in dose to the primary site from 21 Gy to 18 Gy.Methods and Materials: After induction chemotherapy and GTR, patients with HR-NB were enrolled and treated on an RT dose-reduction prospective trial with 18 Gy hyperfractionated RT given in twice-daily fractions of 1.5 Gy each.Results: The 25 study subjects were 1.6 to 9.5 (median, 4.3) years old at enrollment and included 23 (92%) with stage IV and II (8%) with MYCN-amplified stage III disease. Eleven (44%) were in complete remission (CR), and 14 (56%) had persistence of osteomedullary disease postinduction. Three patients (12%) received proton therapy, and the rest received intensity modulated photon therapy. After a follow-up of 1.8 to 4.2 (median, 3.5) years from initiation of RT, no failures occurred within the RT field; 3 patients had marginal recurrences. The respective 3-year progression-free and overall survival rates were 54.5% and 90.9% for patients in first CR and 42.9% and 76.2% for patients not in metastatic CR. Acute toxicity was negligible.Conclusions: Reduced-dose RT with 18 Gy did not compromise local control or survival outcomes in our cohort of patients with HR-NB after GTR. These findings support assessing further RT dose reduction and validation on a larger, multi-institutional trial. [ABSTRACT FROM AUTHOR]

Penetrating neck injuries are serious as there is a high concentration of vital structures in close proximity to each other in a compressed anatomical area. Penetrating neck injuries can be immediately life threatening due to massive bleeding from vascular structures or due to airway compromise. Injury to the digestive tract in the neck may also result in delayed and potentially life-threatening conditions. The majority (79%) of penetrating neck injuries can be managed conservatively. The clinician caring for such a patient requires a structured and comprehensive approach to managing these injuries. This article will provide a general overview of penetrating neck injuries, including resuscitation, epidemiology, surgical management and the use of appropriate imaging. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15–25%. Owing to the rarity of DSRCT, sample scarcity is a barrier in understanding DSRCT biology and developing effective therapies. Utilizing a novel pair of primary and recurrent DSRCTs, we present the first map of DSRCT genomic breakpoints and the first comparison of gene expression alterations between primary and recurrent DSRCT. Our genomic breakpoint map includes the lone previously published DSRCT genomic breakpoint, the breakpoint from our novel primary/recurrent DSRCT pair, as well as the breakpoints of five available DSRCT cell lines and five additional DSRCTs. All mapped breakpoints were unique and most breakpoints included a 1–3 base pair microhomology suggesting microhomology-mediated end-joining as the mechanism of translocation fusion and providing novel insights into the etiology of DSRCT. Through RNA-sequencing analysis, we identified altered genes and pathways between primary and recurrent DSRCTs. Upregulated pathways in the recurrent tumor included several DNA repair and mRNA splicing-related pathways, while downregulated pathways included immune system function and focal adhesion. We further found higher expression of the EWSR1-WT1 upregulated gene set in the recurrent tumor as compared to the primary tumor and lower expression of the EWSR1-WT1 downregulated gene set, suggesting the EWSR1-WT1 fusion continues to play a prominent role in recurrent tumors. The identified pathways including upregulation of DNA repair and downregulation of immune system function may help explain DSRCT's high rate of recurrence and can be utilized to improve the understanding of DSRCT biology and identify novel therapies to both help prevent recurrence and treat recurrent tumors. [ABSTRACT FROM AUTHOR]

Background: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. Patients and methods: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. Results: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. Conclusions: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. Trial registration: clinicaltrials.gov NCT00089245, August 5, 2004. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma.Methods and Materials: After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT.Results: Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P=.01). There was also a trend toward inferior local control with MYCN-amplified tumors or serum lactate dehydrogenase ≥1500 U/L (P=.09 and P=.06, respectively).Conclusion: After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR. [ABSTRACT FROM AUTHOR]

Achieving a cure for metastatic neuroblastoma remains a challenge despite sensitivity to chemotherapy and radiotherapy. Most patients achieve remission, but a failure to eliminate minimal residual disease (MRD) often leads to relapse. Immunotherapy is potentially useful for chemotherapy-resistant disease and may be particularly effective for low levels of MRD that are below the threshold for detection by routine radiological and histological methods. Disialoganglioside (GD2), a surface glycolipid antigen that is ubiquitous and abundant on neuroblastoma cells is an ideal target for immunotherapy. Anti-GD2 monoclonal antibodies currently form the mainstay of neuroblastoma immunotherapy and their safety profile has been well-established. Although responses in patients with gross disease have been observed infrequently, histologic responses of bone marrow disease are consistently achieved in >75 percent of patients with primary refractory neuroblastoma. The advent of highly sensitive and specific molecular assays to measure MRD has confirmed the efficacy anti-GD2 antibody immunotherapy in patients with subclinical disease. Such markers will allow further optimization of other anti-MRD therapies. We review the current status of anti-GD2 clinical trials for neuroblastoma and novel preclinical GD2-targeted strategies for this rare but often lethal childhood cancer. [ABSTRACT FROM AUTHOR]

The article focuses on the authors' views on neuroblastoma, which is defined as an embryonic neoplasm of the sympathetic nervous system. The authors say that neuroblastoma is considered to be the most common extracranial solid tumor of childhood. They refer to the data, which reveals that 90 percent of around 650 cases diagnosed annually in the U.S. affect infants and toddlers. Random genetic mutations are seen as the contributing factors of neuroblastoma.

The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types. [ABSTRACT FROM AUTHOR]

The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types. [ABSTRACT FROM AUTHOR]