Narrative review-diagnosing and managing malignant epidural spinal cord compression: an evidence-based approach.

Background and Objective: Malignant spinal cord compression (MSCC) is a medical emergency. Clinical deterioration can occur quickly and irreversibly. MSCC is caused predominantly by metastatic cancer spread to the epidural space by epithelial or haematological malignancies. The primary diagnostic test is full-spine magnetic resonance imaging (MRI) since it has excellent soft tissue spatial resolution, and MSCC is multi-level in around one-third of cases. The modalities of therapy for MSCC are steroids, radiotherapy, and surgery. Radiotherapy is a mainstay of treatment since indications for surgery are limited. Recently randomised clinical trials exploring long course vs. short course radiotherapy have been undertaken as well as novel incorporation of stereotactic ablative radiotherapy (SABR). This review summarises these recent trials and identifies and discusses published data for novel treatment paradigms of MSCC. Methods: Multiple medical databases were searched through January 7th, 2023 and identified relevant studies that examined the use of radiotherapy with or without surgery in the management of MSCC. Key Content and Findings: In addition to a detailed overview of the pathophysiology and diagnosis of cord compression, we also examine all recent phase III clinical trials to date on the use of conventional radiotherapy in managing MSCC. Our review also provides a comprehensive summary and discussion of the novel approaches to the management of cord compression, including the role of SABR and a non-traditional surgical approach as well. Conclusions: Shorter courses of radiotherapy can be considered for poor prognosis patients. For favourable prognosis patients, longer courses of treatment provide more durable local control. An emerging treatment paradigm is a hybrid approach of surgery and SABR, however this has not been studied prospectively.

Oncogenic alterations reveal key strategies for precision oncology in melanoma treatment.

Background: Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid tumors, including melanomas, to identify potential drug targets. However, the association between clinical outcomes and the molecular alterations has not yet been fully clarified. Methods: A total of 108 patients with melanoma were included in this study, 95 of whom had both sequencing data and clinical outcomes were collected. We analyzed the genetic alterations of 108 malignant melanoma patients using the OncoCare panel, which covers 559 genes. Results: A model was also established to predict side effects through a combination analysis of clinical data and somatic variants, yielding an area under the receiver operating characteristic curve (AUROC) score of 0.8. We also identified epidermal growth factor receptor (EGFR) mutation was excellent predictor for progression-free survival (PFS) for patient who received immunotherapy (log-rank P=0.01), while tumor mutation burden (TMB) was found to not be significantly associated with PFS (log-rank P=0.87). Combining clinical features with genetic analysis, we found that patients carrying both DNA POLD1/ALOX12B or POLD1/PTPRT mutations had a significantly lower survival rate. Conclusions: Overall, these results demonstrate the benefits of applying NGS clinical panels and shed light on future directions of personalized therapeutics for the treatment of melanoma.

Role of ROR2 in promoting gastric cancer metastasis by enhancing c-JUN-mediated MMP3 transcription.

Background: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a transmembrane receptor that has a complex role in cancer, acting either to promote or inhibit tumor progression in different tumor types. The effect of ROR2 on gastric cancer is unclear. Methods: Immunohistochemistry was used to investigate the role of ROR2 in the prognosis of gastric cancer. Transwell assay and a BALB/c nude mice pulmonary metastasis model were used to ascertain the role of ROR2 in promoting metastasis in vitro and in vivo. A protein expression array, chromatin immunoprecipitation (ChIP) assay, and luciferase reporter assay were employed to search for the target genes of ROR2. Results: ROR2 was found to be upregulated in gastric cancer tissues, which was correlated with poor disease-free survival (DFS) and overall survival (OS) in gastric cancer patients. Moreover, ROR2 promoted gastric cancer cell migratory and invasive behaviors in vitro and metastasis in vivo. Further research showed that ROR2 promoted gastric cancer metastasis via upregulation of matrix metalloproteinase 3 (MMP3). Analyses of clinical data indicated that high expression of ROR2 was correlated with a high expression of MMP3. Further study showed that ROR2 activated c-JUN by translocating phosphorylated JNK1/2 into the nucleus, and c-JUN interacted directly with the MMP3 promoter, leading to enhanced MMP3 transcription. Conclusions: We report for the first time that ROR2 is upregulated in gastric cancer, promotes metastasis, and is associated with poor prognosis in gastric cancer. The findings suggest that ROR2 may be a promising prognostic predictor for gastric cancer. Silencing the JNK1/2-c-JUN pathway, thereby inhibiting MMP3 expression, may serve as a promising strategy to inhibit gastric cancer progression.

Bioinformatic analysis of cancer-associated fibroblast related gene signature as a predictive model in clinical outcomes and immune characteristics of gastric cancer.

Background: Gastric cancer (GC) has a high incidence and high mortality rate among Asian countries, and distinguishing predictive prognosis biomarkers for GC are essential. Cancer-associated fibroblasts (CAFs) play a significant role in the progression, immune evasion, and therapeutic resistance of GC. Therefore, CAF-associated genes might have huge potential as prognostic biomarkers for predicting tumor progression and survival rate in GC pateints. Methods: A sum of 1,134 GC patients from the The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD), GSE62254, and GSE84437 datasets as well as GC cohorts from Xijing hospital were included. Firstly, we performed univariate Cox regression analysis to identify CAF-associated prognostic genes. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to develop a CAF gene signature (CAFGS) in the TCGA-STAD training cohort. CAFGS's predictive performance was examined in both the training and validation cohorts, and the relationship between CAFGS and the tumor microenvironment (TME) was investigated by ssGSEA, CIBERSORT, TIMER, and ESTIMATE. Finally, a nomogram of CAFGS was established. Results: Ten CAF-associated genes (ANGPTL4, CPNE8, CST2, HTR1F, IL1RAP, NR1D1, NTAN1, OLFML2B, TMEM259, and VTN) were identified to develop CAFGS. A high CAFGS score represented a worse outcome for GC patients in four cohorts, and a strong correlation was found between CAFGS and the infiltration of immune cells. We showed that CAFs contribute to immune evasion and unfavorable prognoses of GC patients by promoting the formation of an immunosuppressive microenvironment, and a high level of CAF infiltration may attenuate the efficacy of immunotherapy. The nomogram based on CAFGS showed reasonable predictive ability and may deliver great clinical net benefits. Conclusions: We established a CAFGS model with 10 CAF-associated genes that had a great predictive value for GC prognosis and survival rate evaluation. This study could provide a novel insight for investigating the role of CAFs in GC.

Radiotherapy planning of lymphomas: role of metabolic imaging with PET/CT.

Accurate target delineation is an absolute requirement for modern radiotherapy planning. Historically, structural imaging modalities have been used for this purpose, but there is a considerable role for functional imaging with PET/CT to contribute in this area. PET/CT's role in radiotherapy planning is well established and its use is indispensable in the clinical management of the lymphomas, particularly Hodgkin Lymphoma. A crucial use of PET/CT is as a baseline scan for delineation of the initial lymphomatous involvement, since this will determine the contouring of the gross-, clinical- and planning-target volumes (GTV, CTV, PTV). This article reviews the principles of contemporary radiotherapy, examines the evidence for the contribution of PET/CT to radiotherapy planning in lymphoma and the practicalities and challenges of applying this powerful technology to this situation.

Radiation recall reactions: An oncologic enigma.

Radiation recall reactions (RRR) are uncommon but are a well-known phenomenon to oncologists. Tissue damage in a prior irradiation portal is 'recalled' after the administration of a drug, historically cytotoxics, or more recently, targeted or immunotherapeutic agents. Even COVID-19 vaccines are a reported cause. RRR are enigmatic in that their cause is unknown, but they generally have the histopathological and clinical features of acute or chronic inflammation. They can occur in a variety of tissues, the commonest being skin, which accounts for two-thirds of reported cases. They are generally relatively mild and self-limiting once the trigger drug is stopped, although severe cases with tissue necrosis have occurred. Rechallenge with drug does not necessarily cause reactivation of the reaction. Symptomatic treatment with steroids and antihistamines are usually effective, but their impact on the clinical course is unclear. Various hypotheses have been proposed as to the mechanism of RRR; a non-immune fixed drug reaction-like condition, dysregulated release of reactive oxygen species, abnormalities of tissue vasculature and impaired DNA repair. All could lead to a characteristic inflammatory microenvironment, resulting in dysfunction of tissue stem cells, keratinocyte necrosis and dermal abnormalities. Alternatively or in addition, low levels of inflammatory tissue cytokines induced by previous irradiation might be further upregulated by drug exposure. Most information in this review refers to data derived from cutaneous RRR, since they are the most common form reported.

Cutaneous chemotherapy-induced radiation recall reaction.

Chemotherapy-induced radiation recall reactions are rare, commonly affecting skin but can affect internal organs. Treatments include antihistamines and topical steroids and discontinuation of therapy if severe. Rechallenge may not cause recurrence.

Pathobiology, irradiation dosimetric parameters and therapy of radiation-induced gastric damage: a narrative review.

OBJECTIVE: To review the pathobiology, irradiation dosimetric parameters and other risk factors, and therapy of radiation-induced gastric damage (RIGD). BACKGROUND: RIGD is a side-effect of upper abdominal radiotherapy. Acute toxicities are usually mild and self-limiting. Late toxicities are potentially life-threatening and include bleeding, perforation or stenosis. The data on RIGD is mainly historical and derived from neoplasms and treatments where the role of radiotherapy is contracting, such as para-aortic nodal irradiation for testis and cervical cancer and Hodgkin's Disease. On the other hand, the role of radiotherapy is expanding, especially with stereotactic body radiotherapy (SBRT) treatments evolving for both primary and secondary upper gastrointestinal neoplasms, which might be expected to increase the frequency of RIGD. Pathoclinical and radiation dosimetric data which might predict the risk of RIGD are evaluated. METHODS: English language articles between 1945 and December 2020, using PubMed and Embase, searching titles for keywords including: radiation; ionizing; radiotherapy; gastritis and 65 articles were selected for review. There may have been a risk of bias in the studies evaluated, since the majority of reports were retrospective, largely descriptive and qualitative. CONCLUSIONS: A common pathoclinical theme in RIGD is inflammation. Numerous factors predict for a greater likelihood of RIGD, including radiation fraction size and dose, concurrent chemotherapy and previous abdominal surgery. Therapy is pathology-dependent and comprises pharmacological, interventional and in the most severe cases, surgical approaches. It is timely to review the topic of RIGD, discuss the limitations of the data and highlight the need for future research directions.

A Roberts Syndrome Individual With Differential Genotoxin Sensitivity and a DNA Damage Response Defect.

PURPOSE: Roberts syndrome (RBS) is a rare, recessively transmitted developmental disorder characterized by growth retardation, craniofacial abnormalities, and truncation of limbs. All affected individuals to date have mutations in the ESCO2 (establishment of cohesion 2) gene, a key regulator of the cohesin complex, which is involved in sister chromatid cohesion and DNA double-strand break (DSB) repair. Here we characterize DNA damage responses (DDRs) for the first time in an RBS-affected family. METHODS AND MATERIALS: Lymphoblastoid cell lines were established from an RBS family, including the proband and parents carrying ESCO2 mutations. Various DDR assays were performed on these cells, including cell survival, chromosome break, and apoptosis assays; checkpoint activation indicators; and measures of DNA breakage and repair. RESULTS: Cells derived from the RBS-affected individual showed sensitivity to ionizing radiation (IR) and mitomycin C-induced DNA damage. In this ESCO2 compound heterozygote, other DDRs were also defective, including enhanced IR-induced clastogenicity and apoptosis; increased DNA DSB induction; and a reduced capacity for repairing IR-induced DNA DSBs, as measured by γ-H2AX foci and the comet assay. CONCLUSIONS: In addition to its developmental features, RBS can be, like ataxia telangiectasia, considered a DDR-defective syndrome, which contributes to its cellular, molecular, and clinical phenotype.

Molecular Imaging Using PET/CT for Radiation Therapy Planning for Adult Cancers: Current Status and Expanding Applications.

Accurate tumor delineation is a priority in radiation therapy (RT). Metabolic imaging has a key and evolving role in target volume selection and delineation. This is especially so for non-small cell lung cancer, squamous cell cancer of the head and neck, and lymphoma, for which positron emission tomography/computed tomography (PET/CT) is complimentary to structural imaging modalities, not only in delineating primary tumors, but also often in revealing previously undiagnosed regional nodal disease. At some sites, PET/CT has been confirmed to enable target size reduction compared with structural imaging alone, with enhanced normal tissue sparing and potentially allowing for dose escalation. These contributions often dramatically affect RT strategies. However, some limitations exist to the use of fluorodeoxyglucose-PET in RT planning, including its relatively poor spatial resolution and partial voluming effects for small tumors. A role is developing for contributions from metabolic imaging to RT planning at other tumor sites and exciting new applications for the use of non-fluorodeoxyglucose metabolic markers for RT planning.

Erratum to non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype.

[This corrects the article DOI: 10.21037/atm.2017.03.04.].

Hairy cell leukaemia variant with periarticular joint infiltration and excellent radiotherapy response.

Hairy cell leukaemia (HCL) is rare, accounting for only 2% of leukaemias. An even more infrequent variant has been described, HCL-V. The clinicopathologic features of these two entities overlap significantly, although they differ in a number of aspects, including demographics and immunophenotype. In this report, we present the case of a man with HCL-V diagnosed 12 years previously, who is currently haematologically stable with an unusual complication of joint pain due to extensive bony expansion secondary to leukaemic infiltration, and atypical skeletal imaging. His painful joint disease responded dramatically to radiotherapy.

A radiation-induced and radiation-sensitive, delayed onset angiosarcoma arising in a precursor lymphangioendothelioma.

An 83-year-old female was treated with mastectomy and postoperative radiotherapy for breast cancer 30 years prior to developing a new small patch of thickening and scaliness on her left upper back, within the previous radiotherapy field. Serial excision biopsies revealed this to be a lymphangioendothelioma with no suggestion of malignancy. In early 2006 the lesion began to enlarge and take on a more erythematous plaque-like appearance. She was reviewed by a specialist dermatologist and an excision biopsy revealed a low-grade cutaneous angiosarcoma; this was approximately 38 years after radiotherapy to this region, the longest reported period between irradiation and in-field angiosarcoma development (the previous being 16 years). To our knowledge, this is the first case of post-radiotherapy angiosarcoma with a diagnosed precursor lesion. The lesion was treated with surgical excision and adjuvant radiotherapy. After further in- and out of- field recurrences, low dose radiotherapy elicited a surprisingly rapid and complete response within the treated areas; this was unusual in that these tumours are characteristically radiation-resistant. The radiosensitive case we report here raises the possibility that radiation should be more widely considered in the therapy of this disease. Methods of treatment of this rare malignancy are discussed.

In vitro prediction of breast cancer therapy toxicity.

BACKGROUND: Understanding the basis of clinical radiosensitivity is a key goal of radiation research. In this study, we used the limiting dilution assay (LDA) to analyze in vitro radiosensitivity of cell lines from individuals with breast and other cancers, who had been treated with ionizing radiation, and who either had a non-radiosensitive (RS) radiation response or who were clinically RS. METHODS: Lymphoblastoid cell lines (LCLs) were created from 29 cancer patients including 19 RS patients, 10 controls who had not developed severe normal tissue reactions, and 1 ataxia telangiectasia RS control cell line. The clinically RS patients had grade 3 or grade 4 reactions; one had a grade 2 reaction. All cells were exposed to graded doses of gamma-radiation in vitro and cell survival assessed via LDA. Cell survival was expressed on non-linear regression analysis-fitted survival curves and also as the surviving fraction at 2 Gray (Gy) (SF2). RESULTS: Our LDA analysis yielded two notable positive results. Firstly, it could distinguish control cells from cells from pooled breast cancer cases with severe reactions of all types (acute reactors, consequential late reactors and late reactors). Secondly, two radiosensitivity outliers were detected on the fitted curves, corresponding clinically to grade 3 and 4 late radiation reactions in breast and head and neck cancer cases respectively. The assay showed considerable cell survival heterogeneity. CONCLUSIONS: The LDA as used here may provide unique clinical utility in detecting potential RS breast cancer patients prior to radiotherapy (RT), a form of personalized medicine. The assay may be especially useful in situations where its results can be temporally available prior to therapy initiation (e.g., those patients not undergoing RT until some months after surgery, typically those having adjuvant chemotherapy prior to RT). Two LCLs from RS outliers could potentially yield insight into the cellular and/or genetic basis of radiosensitivity, for example by undertaking genomic analyses on these cell lines.

Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype.

BACKGROUND: Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. METHODS: We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse-transcriptase polymerase chain reaction and pulsed-field gel electrophoresis. RESULTS: We hypothesized that abnormalities in expression of these proteins may explain the radiosensitivity of some of our cancer patients. The cells from one patient showed a reproducibly consistent expression reduction in two complex-forming DNA double-strand break repair protein components (DNA Ligase IV and XRCC4). We also showed a corresponding reduction in both gene products at the mRNA level. Additionally, the mRNA inducibility by ionizing radiation was increased for one of the proteins in the patient's cells. We confirmed the likely functional significance of the non-homologous end-joining (NHEJ) expression abnormalities with a DNA double strand break (DNA DSB) repair assay. CONCLUSIONS: We have identified a novel biological phenotype linked to clinical radiosensitivity. This is important in that very few molecular defects are known in human radiotherapy subjects. Such knowledge may contribute to the understanding of radiation response mechanisms in cancer patients and to personalization of radiotherapy.

Primary psoas sarcoma causing malignant psoas syndrome: favourable response to radiotherapy.

Malignant psoas syndrome (MPS) is an uncommon condition first described by Stevens et al. MPS is caused by malignant infiltration of the psoas muscle and adjacent nerves and is characterised by (fixed) flexion deformity of the ipsilateral hip and proximal lumbosacral plexopathy. It has previously been described in relation to metastatic carcinoma, melanoma and liposarcoma, as well as non-Hodgkins lymphoma. We present the case of a 68-year-old woman with a sarcoma arising in the left psoas muscle at the level of L4 who presented with symptoms of MPS. To the authors' knowledge this is the first case of MPS arising from a primary sarcoma of the iliopsoas compartment. The patient underwent presurgical radiotherapy, with a significant improvement in pain control without an increase in analgesic medications. We discuss the aetiology of MPS and the role of radiotherapy in the treatment of this rare syndrome.

Toxicity and dosimetric analysis of non-small cell lung cancer patients undergoing radiotherapy with 4DCT and image-guided intensity modulated radiotherapy: a regional centre's experience.

INTRODUCTION: For patients receiving radiotherapy for locally advance non-small cell lung cancer (NSCLC), the probability of experiencing severe radiation pneumonitis (RP) appears to rise with an increase in radiation received by the lungs. Intensity modulated radiotherapy (IMRT) provides the ability to reduce planned doses to healthy organs at risk (OAR) and can potentially reduce treatment-related side effects. This study reports toxicity outcomes and provides a dosimetric comparison with three-dimensional conformal radiotherapy (3DCRT). METHODS: Thirty curative NSCLC patients received radiotherapy using four-dimensional computed tomography and five-field IMRT. All were assessed for early and late toxicity using common terminology criteria for adverse events. All plans were subsequently re-planned using 3DCRT to the same standard as the clinical plans. Dosimetric parameters for lungs, oesophagus, heart and conformity were recorded for comparison between the two techniques. RESULTS: IMRT plans achieved improved high-dose conformity and reduced OAR doses including lung volumes irradiated to 5-20 Gy. One case each of oesophagitis and erythema (3%) were the only Grade 3 toxicities. Rates of Grade 2 oesophagitis were 40%. No cases of Grade 3 RP were recorded and Grade 2 RP rates were as low as 3%. CONCLUSION: IMRT provides a dosimetric benefit when compared to 3DCRT. While the clinical benefit appears to increase with increasing target size and increasing complexity, IMRT appears preferential to 3DCRT in the treatment of NSCLC.