Site Of Disease Research Articles

Diagnostic criteria for amyotrophic lateral sclerosis.

The present review will discuss the evolution of diagnostic criteria for amyotrophic lateral sclerosis (ALS) and biomarker considerations. To address the limitations of existing ALS diagnostic criteria, a consortium of key stakeholders developed the Gold Coast consensus criteria (GCC). The GCC has similar or greater sensitivity compared with the revised El Escorial (rEEC) and Awaji criteria (AC), particularly for atypical phenotypes, maintained across disease duration, severity, and site of onset. In addition to improving diagnostic sensitivity, using the GCC in clinical trials may promote an increased enrolment of up to 50% of ALS patients who do not currently meet the full diagnostic eligibility requirements of the rEEC. Future inclusion of genetic biomarkers may mitigate some limitations of the GCC, to further improve diagnostic utility. In advance of such a process, validation of these biomarkers will be required before inclusion as additional criteria. The GCC are simpler to use than previous consensus criteria, with demonstrated greater sensitivity and, enabling an earlier and more definitive ALS diagnosis, thereby facilitating wider enrolment into clinical trials. Broader implementation of the GCC in clinical trial settings is currently underway, globally.

Oncological and functional outcomes of pathological fractures of lower extremities in patients with malignant bone tumors.

As managing pathological fractures of the extremities can be difficult, the present study aimed to present a treatment algorithm for lower extremity bone malignancies. A total of 38 patients with impending and pathological fractures were treated at the Department of Orthopedic Surgery in Kindai University Hospital. Age, sex, fracture site, type of primary malignancy, number of metastases, pre-fracture Eastern Cooperative Oncology Group performance status (ECOG-PS) score, adjuvant therapy, treatment modality, operative time, blood loss, postoperative complications, Musculoskeletal Tumor Society (MSTS) score, outcomes, follow-up period and the MSTS scores and ECOG-PS were compared in cases of primary malignant tumors and those cases of metastatic malignant tumors were retrospectively surveyed. Post-treatment MSTS scores in cases of impending and pathological fractures were compared between intramedullary nail fixation and non-intramedullary nail fixation procedures. Disease sites included the sub-trochanteric femur in 10 patients, trochanteric femur in 8, femoral diaphysis in 7, femoral neck in 5, bilateral trochanteric femur in 3, proximal tibia in 3 and distal femur in 2 patients. A total of 10 patients had metastases between 3-20 sites. The median pre-fracture ECOG-PS score was 1. Adjuvant radiotherapy was administered to 5, chemotherapy to 8 and radiotherapy with chemotherapy to 10 patients. Surgical procedures included intramedullary nails in 18 patients, tumor arthroplasty in 4, plate fixation in 3, artificial head replacement in three, compression hip screw (CHS) in 3, conservative treatment in 2, bilateral intramedullary nail fixation in 2 and artificial bone stem with combined intramedullary nail and plate fixation, right-sided artificial head replacement and left-sided CHS in 1 patient each. The MSTS score was 19.9±8.95 for intramedullary nail fixation and 24.3±7.45 for other procedures, with a negative association between the MSTS score and pre-fracture ECOG-PS. The median follow-up period was 8 months. The outcomes were as follows: Alive with disease, 23 patients; continued disease-free, 1 patient; and dead due to disease, 14 patients. The 1-year postoperative overall survival rate was 60.5%. Moreover, the group with metastatic malignant tumors, which had significantly worse ECOG-PS, had significantly lower MSTS scores than the group with primary malignant tumors. The authors' treatment algorithm for malignant bone tumors of the lower extremity was shown to be useful.

Extensive Multiorgan and Neurological Involvement on F-18 FDG PET-CT in a Case of Rosai-Dorfman Disease

AbstractRosai-Dorfman disease (RDD) is a rare benign proliferative disorder. Lymph nodes are the usual and common sites of involvement. Involvement of the extranodal site is also documented in the literature. 18F-fluorodeoxyglucose positron emission tomography computed tomography (F18-FDG PET CT) is a valuable whole-body imaging modality in staging and treatment response of various lymphoproliferative and solid organ malignancy. Similarly, PET CT survey can detect the involved sites of various body systems, infective or inflammatory diseases, and provide guidance for biopsy and to reach to diagnosis. Here, we present a case of RDD, who presented with neurological manifestations and on F18-FDG PET CT, diagnosed with multiorgan involvement.

Clinical Features and Histopathological Analysis of Oral Lichen Planus: An Analysis of 105 Chinese Patients.

To study the clinical and pathological characteristics of oral lichen planus (OLP) in a large sample. A comprehensive analysis was conducted on 105 patients with oral lichen planus (OLP), considering various factors including sex, age, disease site, lesion type, lesion area, morphological characteristics, self-reported symptoms, and history of systemic diseases. Histopathological examination was performed for each patient, and the pathology results were analysed according to sex and age group. 70.5% of the OLP patients were female, and OLP was most likely to occur in the cheek, followed by the tongue, lips, gums and palate. The patients with moderate pain according to the VAS score accounted for 60%. Thirty-nine percent of the OLP patients had a systemic disease, and the most common clinical type of OLP was nonerosive. Most of the pathological results showed liquefaction degeneration of basal cells and infiltration of lamina propria lymphocytes. There was no statistically significant difference in pathological manifestations between male and female patients, and there were statistically significant differences in pathological manifestations among different ages patients. This study analysed the sociodemographic data and clinical manifestations of 105 OLP patients to guide follow-up treatment planning and disease monitoring. Moreover, pathological manifestations should be analysed to avoid delayed treatment and to monitor for carcinogenesis. Furthermore, the correlation of pathological manifestations among OLP patients with different sexes and ages is conducive to further research on the specific differential manifestations and possible underlying mechanisms involved.

Bioinspired molecular communications system for targeted drug delivery with IoBNT-based sustainable biocyber interface

This paper presents a sustainable biocyber interface approach for an intelligent targeted drug delivery system (TDDS). The proposed approach employs a bioinspired molecular communications (MC) system in which molecules are used as information carriers and a multi-input multi-output (MIMO) Forster resonance energy transfer (FRET) nanorelay to efficiently transfer therapeutic drugs from extravascular (outside blood vessels) to intravascular (within blood vessels) sites that are targeting diseased tissue. The proposed approach consists of a number of bio-nano things (BNTs) implanted inside the human intra-body nanonetwork near the diseased site. The communication among BNTs is accomplished by a sequential multistep FRET, and the nanonetwork is controlled by the Internet of Bio-Nano Thing (IoBNT) paradigm sustained by an uplink/downlink biocyber interface. The bit error rate (BER) and molecular channel capacity are utilized to evaluate the performance of the proposed approach. In addition, a Markov model decision in terms of the number of nanomachines is presented to calculate the successful probability of drug delivery and the average delay time. The numerical results show how effective the suggested method is at transmitting therapeutic medication information with an attainable bit-rate error.

Use of Drug Sensitisers to Improve Therapeutic Index in Cancer.

The clinical management of malignant tumours is challenging, often leading to severe adverse effects and death. Drug resistance (DR) antagonises the effectiveness of treatments, and increasing drug dosage can worsen the therapeutic index (TI). Current efforts to overcome DR predominantly involve the use of drug combinations, including applying multiple anti-cancerous drugs, employing drug sensitisers, which are chemical agents that enhance pharmacokinetics (PK), including the targeting of cellular pathways and regulating pertinent membrane transporters. While combining multiple compounds may lead to drug-drug interactions (DDI) or polypharmacy effect, the use of drug sensitisers permits rapid attainment of effective treatment dosages at the disease site to prevent early DR and minimise side effects and will reduce the chance of DDI as lower drug doses are required. This review highlights the essential use of TI in evaluating drug dosage for cancer treatment and discusses the lack of a unified standard for TI within the field. Commonly used benefit-risk assessment criteria are summarised, and the critical exploration of the current use of TI in the pharmaceutical industrial sector is included. Specifically, this review leads to the discussion of drug sensitisers to facilitate improved ratios of effective dose to toxic dose directly in humans. The combination of drug and sensitiser molecules might see additional benefits to rekindle those drugs that failed late-stage clinical trials by the removal of detrimental off-target activities through the use of lower drug doses. Drug combinations and employing drug sensitisers are potential means to combat DR. The evolution of drug combinations and polypharmacy on TI are reviewed. Notably, the novel binary weapon approach is introduced as a new opportunity to improve TI. This review emphasises the urgent need for a criterion to systematically evaluate drug safety and efficiency for practical implementation in the field.

Medical imaging in melioidosis - 20-year experience in a non-endemic Australian city.

Melioidosis may occasionally be encountered in non-endemic areas and medical imaging is frequently used to identify and characterise sites of disease. The purpose of this study is to describe the spectrum of imaging findings encountered in melioidosis patients treated in the tertiary public hospitals of Perth, Western Australia, between 2002 and 2022. A database search and electronic medical record review was used to identify cases. Cases were included if they had Burkholderia pseudomallei isolated on culture and if they had at least one diagnostic imaging study performed at a Perth public tertiary hospital. The relevant imaging studies were reviewed, and imaging findings were recorded. Thirty-six cases were identified. The most common disease manifestation was bacteraemia (72%, 26 cases), followed by pulmonary infection (58%, 21 cases), skin and soft tissue infection (22%, eight cases), prostate abscess (14%, five cases) and septic arthritis (6%, two cases). A previously unreported case of isolated melioid pleural effusion was identified, as was a case of reactivated chronic latent pulmonary melioidosis with an apparent delay of over 20 years between the onset of symptoms and the time of infection. In cases with pulmonary melioidosis, the major lung abnormalities on CT chest could be categorised into one of two distinct patterns: nodular-predominant (78%) or consolidation-predominant (22%). Further research is required to assess the utility of the pattern-based categorisation of lung abnormalities on CT chest seen in the pulmonary melioidosis cases of this series.

Tumor-Localized Interleukin-2 and Interleukin-12 Combine with Radiation Therapy to Safely Potentiate Regression of Advanced Malignant Melanoma in Pet Dogs.

Cytokines IL2 and IL12 exhibit potent anticancer activity but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice and was previously safe in pet dogs with sarcoma. Here, we sought to test the efficacy of this approach in dogs with advanced melanoma. This study examined 15 client-owned dogs with histologically or cytologically confirmed malignant melanoma that received a single 9-Gy fraction of radiotherapy, followed by six cycles of combined collagen-anchored IL2 and IL12 therapy every 2 weeks. Cytokine dosing followed a 3 + 3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. Median survival regardless of the tumor stage or dose level was 256 days, and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) had partial responses across their combined lesions, which is evidence of locoregional response. Profiling by NanoString of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.

Do all patients that undergo a ‘complete’ secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer, benefit from it?

Abstract Following the results of three randomized trials (GOG-213, DESKTOP-III, and SOC-1), secondary cytoreductive surgery (sCRS) is recommended as a therapeutic option for all patients with platinum-sensitive recurrence by the NCCN guidelines and for oligometastatic recurrence by the ESMO-ESGO guidelines. Criteria for predicting a complete gross resection (CGR) were used to select patients for sCRS in all three trials. No trial used surgical prognostic factors like disease sites or disease extent for stratification. The outcomes of sCRS varied in preplanned/post-hoc subgroup analyses. The survival following an incomplete CRS was worse than with systemic chemotherapy alone. Not all patients will benefit similarly from sCRS, even if a CGR is obtained. No trial evaluated the benefit of sCRS in patients receiving poly-ADP ribose polymerase (PARP) inhibitors. While GOG-213 showed no benefit of sCRS when bevacizumab was used, the role of bevacizumab in patients having a CGR was not evaluated. The use of targeted therapies during first-line therapy is increasing, affecting treatment decisions and future clinical trial designs. New trials on sCRS should stratify patients according to surgical prognostic factors; sub-group analyses should be performed only in patients with CGR.

Non-invasive strategy: Developing a topical IL-4Rα-specific nanobody for the treatment of allergic airway diseases

Inhibiting IL-4 and IL-13 are critical cytokines that induce the pathogenic responses of allergic airway diseases. Currently, monoclonal antibodies targeting IL-4Rα are administered subcutaneously to treat eosinophilic rhinosinusitis and allergic asthma. However, these treatments have several drawbacks. To address these issues, we have developed a novel IL-4Rα-targeting nanobody designed for non-invasive delivery to local inflammatory sites in allergic airway diseases. H5, selected via the ribosomal display applied screening from synthetic nanobody library, underwent dimerization and in-silico affinity maturation using AlphaFold2 and GROMACS resulting in a substantial/dramatic enhancement of its binding affinity. H5 effectively controlled inflammatory markers such as MUC5AC, CCL26, and FOXJ1 in human nasal epithelial cells (HNECs) by inhibiting IL-4 and IL-13 signaling. The bivalent form of H5 showed efficacy in easily accessible cells, such as multi-ciliated cells, while the monovalent variant targeted hard-to-reach cells, such as basal cells of HNECs. In summary, we developed a nanobody that could effectively inhibit inflammatory signaling in HNECs via intranasal administration, showing promise as a non-invasive rhinitis treatment.

Prospective investigation of amino acid transport and PSMA-targeted positron emission tomography for metastatic lobular breast carcinoma.

To explore the feasibility of imaging amino-acid transport and PSMA molecular pathways in the detection of metastatic breast invasive lobular carcinoma (ILC) and if there is superior detection compared to standard-of-care imaging [computed tomography (CT)/bone scan, or 18F-FDG positron-emission-tomography (PET)-CT]. 20 women with de-novo or suspected metastatic ILC underwent two PET-CT scans with 18F-fluciclovine and 68Ga-PSMA-11 on separate days. Uptake per patient and in 3 regions per patient - ipsilateral axillary lymph node (LN), extra-axillary LN (ipsilateral supraclavicular or internal mammary), or distant sites of disease - was compared to standard-of-care imaging (CT/bone scan in 13 patients and 18F-FDG PET-CT in 7 patients). Results were correlated to a composite standard of truth. Confirmed detection rate (cDR) was compared using McNemar's test. Mean SUVmax of 18F-fluciclovine and 68Ga-PSMA-11 in the most avid lesion for each true positive metastatic region and intact primary lesion were compared by t-test. The cDR for standard-of-care imaging was 5/20 patients in 5/60 regions. 68Ga-PSMA-11 PET-CT detected metastasis in 7/20 patients in 7/60 regions. 18F-fluciclovine PET-CT detected metastasis in 9/20 patients in 12/60 regions. The cDR for 18F-fluciclovine PET-CT was significantly higher versus standard-of-care imaging on the patient and combined region levels, while there were no significant differences between 68Ga-PSMA-11 and standard-of care imaging. 18F-fluciclovine cDR was also significantly higher than 68Ga-PSMA-11 on the combined region level. Mean SUVmax for true positive metastatic and primary lesions with 18F-fluciclovine (n = 18) was significantly greater than for 68Ga-PSMA-11 (n = 11) [5.5 ± 1.8 versus 3.5 ± 2.7 respectively, p = 0.021]. In this exploratory trial, 18F-fluciclovine PET-CT has a significantly higher cDR for ILC metastases compared to standard-of-care imaging and to 68Ga-PSMA-11. Mean SUVmax for true positive malignancy was significantly higher with 18F-fluciclovine than for 68Ga-PSMA-11. Exploratory data from this trial suggests that molecular imaging of amino acid metabolism in patients with ILC deserves further study. Early phase (I-II) clinical trial (NCT04750473) funded by the National Institutes of Health (R21CA256280).

Delivery of Inhaled Medication in Children: Revisiting Pharmacological and Practical Issues for Better Health Outcome

For safe and effective therapy of respiratory disorders in children, delivering the medication at the site of disease i.e. directly into the respiratory tract via aerosolized medication is critical. But, the anatomical and physiological differences in the respiratory tract of infants/children and adults make the delivery of aerosolized medication complicated. This review article gives an overview of the delivery of inhaled medication in children and discuss the pharmacological and specific clinically relevant aspects of medication delivery using nebulizers, pressurized metered dose inhalers (MDIs), and dry powder inhalers (DPIs) in children. As a physician, one should always keep in mind the various factors like properties of the device, aerosol particle, patient factors such as disease state, ventilatory pattern, and administration technique that can affect drug deposition via aerosol delivery devices.

Exploring the interactions of JAK inhibitor and S1P receptor modulator drugs with the human gut microbiome: Implications for colonic drug delivery and inflammatory bowel disease

The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process.

Treatment Terminations During Radiation Therapy: A 10-Year Experience

Patients undergoing radiation therapy may terminate treatment for any number of reasons. The incidence of treatment termination (TT) during radiation therapy has not been studied. Herein we present a cohort of TT at a large multi-center radiation oncology department over 10 years. TTs between 1/2013 and 1/2023 were prospectively analyzed as part of an ongoing departmental quality and safety program. TT was defined as any premature discontinuation of therapy after initiating radiation planning. The rate of TT was calculated as a percentage of all patients starting radiation planning. All cases were presented at monthly morbidity and mortality (MM) conferences with a root cause reviewed (RCA). A total of 1,448 TTs were identified out of 31,199 planned courses of care (4.6%). Six hundred eighty-six (47.4%) involved patients treated with curative intent, while 753 (52.0%) with palliative intent, and 9 (0.6%) for benign disease. The rate of TT decreased from 8.49% in 2013 to 3.02% in 2022 with rates decreasing yearly. The most common disease sites for TT were CNS (21.7%), H&N (19.3%), Thorax (17.5%), and Bone (14.2%). The most common causes of TT were hospice and/or patient expiration (35.9%), patient choice unrelated to toxicity (35.2%), and clinician choice unrelated to toxicity (11.5%). This 10-year prospective review of TTs identified a year-over-year decrease in TTs as a percentage of planned patients. This decrease may be associated with the addition of RCA for TTs and discussion monthly at MM rounds, coupled with departmental upstream quality initiatives implemented over time. Understanding the reasons behind TTs may help to decrease preventable TTs. While some TTs may be unavoidable, open discourse and quality improvement changes effectively reduce TT incidents over time.

Blood RNA signatures outperform CRP triage of tuberculosis lymphadenitis and pericarditis.

Limited data are available on the diagnostic accuracy of blood RNA biomarker signatures for extrapulmonary TB (EPTB). We addressed this question among people investigated for TB lymphadenitis and TB pericarditis, in Cape Town, South Africa. We enrolled 440 consecutive adults referred to a hospital for invasive sampling for presumptive TB lymphadenitis (n=300) or presumptive TB pericarditis (n=140). Samples from the site of disease underwent culture and/or molecular testing for Mycobacterium tuberculosis complex (Mtb). Discrimination of patients with and without TB defined by microbiology or cytology reference standards was evaluated using seven previously reported blood RNA signatures by area under the receiver-operating characteristic curve (AUROC) and sensitivity/specificity at predefined thresholds, benchmarked against blood C-reactive protein (CRP) and the World Health Organization (WHO) target product profile (TPP) for a TB triage test. Decision curve analysis (DCA) was used to evaluate the clinical utility of the best performing blood RNA signature and CRP. Data from 374 patients for whom results were available from at least one microbiological test from the site of disease, and blood CRP and RNA measurements, were included. Using microbiological results as the reference standard in the primary analysis (N=204 with TB), performance was similar across lymphadenitis and pericarditis patients. In the pooled analysis of both cohorts, all RNA signatures had comparable discrimination with AUROC point estimates ranging 0.77-0.82, superior to that of CRP (0.61, 95% confidence interval 0.56-0.67). The best performing signature (Roe3) achieved an AUROC of 0.82 (0.77-0.86). At a predefined threshold of 2 standard deviations (Z2) above the mean of a healthy reference control group, this signature achieved 78% (72-83%) sensitivity and 69% (62-75%) specificity. In this setting, DCA revealed that Roe3 offered greater net benefit than other approaches for services aiming to reduce the number needed to investigate with confirmatory testing to <4 to identify each case of TB. RNA biomarkers show better accuracy and clinical utility than CRP to trigger confirmatory TB testing in patients with TB lymphadenitis and TB pericarditis, but still fall short of the WHO TPP for TB triage tests. South African MRC, EDCTP2, NIH/NIAID, Wellcome Trust, NIHR, Royal College of Physicians London. Evidence before this study: Blood RNA biomarker signatures and CRP measurements have emerged as potential triage tests for TB, but evidence is mostly limited to their performance in pulmonary TB. Microbiological diagnosis of extrapulmonary TB (EPTB) is made challenging by the need for invasive sampling to obtain tissue from the site of disease. This is compounded by lower sensitivity of confirmatory molecular tests for EPTB compared to their performance in pulmonary disease. We performed a systematic review of diagnostic accuracy studies of blood RNA biomarkers or CRP measurements for EPTB, which could mitigate the need for site-of-disease sampling for the diagnosis of TB. We searched PubMed up to 1 st August 2023, using the following criteria: "extrapulmonary [title/abstract] AND tuberculosis [title/abstract] AND biomarker [title/abstract]". Although extrapulmonary TB was included in several studies, none focused specifically on EPTB or included an adequate number of EPTB cases to provide precise estimates of test accuracy. Added value of this study: To the best of our knowledge, we report the first diagnostic accuracy study of blood RNA biomarkers and CRP for TB among people with EPTB syndromes. We examined the performance of seven previously identified blood RNA biomarkers as triage tests for TB lymphadenitis and TB pericarditis compared to a microbiology reference standard among people referred to hospital for invasive sampling in a high TB and HIV prevalence setting. Multiple blood RNA biomarkers showed comparable diagnostic accuracy to that previously reported for pulmonary TB in both EPTB disease cohorts, irrespective of HIV status. All seven blood RNA biomarkers showed superior diagnostic accuracy to CRP for both lymphadenitis and pericarditis, but failed to meet the combined >90% sensitivity and >70% specificity recommended for a blood-based diagnostic triage test by WHO. Nonetheless, in decision curve analysis, an approach of using the best performing blood RNA biomarker to trigger confirmatory microbiological testing showed superior clinical utility in clinical services seeking to reduce the number needed to test (using invasive confirmatory testing) to less than 4 for each EPTB case detected. If acceptable to undertake invasive testing in more than 4 people for each true case detected, then a test-all approach will provide greater net benefit in this TB/HIV hyperendemic setting.Implications of all the available evidence: Blood RNA biomarkers show some potential as diagnostic triage tests for TB lymphadenitis and TB pericarditis, but do not provide the level of accuracy for blood-based triage tests recommended by WHO for community-based tests. CRP has inferior diagnostic accuracy to blood RNA biomarkers and cannot be recommended for diagnostic triage among people with EPTB syndromes referred for invasive sampling.

Metastatic diseases to the adrenal gland: A comprehensive study from an academic institution with emphasis on clinical occult cases

The adrenal gland is one of the common sites of metastasis and distinguishing metastatic diseases from adrenal primary neoplasms is essential for accurate clinical management of patients. Our study aimed to elucidate the spectrum and clinicopathologic features of metastatic solid tumors to the adrenal gland at an academic institution, with special focus patients presented with solitary adrenal masses without previously known malignancies. Our departmental database (2013–2022) was retrospectively searched and 129 patients with metastatic solid tumors involving the adrenal gland were identified. The median age at the initial diagnosis of metastatic diseases was 64 years old (range, 54–70 years). The majority of the diseases were presented as unilateral (n=118) or unifocal (n=119) involvement. Most patients had known prior or concurrent malignancies (n=125), whereas adrenal gland involvement was the initial clinical presentation in 4 patients. The most common primary carcinomas included renal cell carcinoma (n=84), lung adenocarcinoma (n=21), urothelial carcinoma (n=3) and hepatocellular carcinoma (n=3). In 104 (80 %) patients with available follow up (median of 39 months, ranging 0–81 months), 43 patients died of disease. Metastatic diseases are usually exercised in the differential diagnosis when there is clinically known malignant primary. In patients without clinical known malignancies, close clinical and radiologic correlation and thorough relevant clinical work up are critical, because clinical occult malignancy may metastasize to the adrenal gland as a solitary mass at the initial presentation, although it is rare.

Ablative Radiation Therapy to Restrain Everything Safely Treatable (ARREST): A Phase 1 Study of Stereotactic Ablative Radiation Therapy for Polymetastatic Disease

This phase 1 study aimed to assess the safety and feasibility of SABR therapy delivery to all sites of polymetastatic disease (>10 metastases). A 3 + 3 study design was used with 5 dose levels from 6 Gy (6 Gy × 1) to 30 Gy (6 Gy weekly × 5). Dose-limiting toxicity (DLT) was defined as any grade 4 or 5 toxicity or more than 3 grade 3 toxicities within 6 weeks of treatment. The primary endpoint was the maximal tolerated dose, defined as the dose level where ≥2/6 of patients experienced DLT. Secondary endpoints included quality of life (Functional Assessment of Cancer Therapy - General and European Quality of Life 5 Dimension 5 Level) at 6 weeks posttreatment, progression-free survival, and overall survival. Thirteen patients were accrued: 12 Gy (n = 3), 18 Gy (n = 3), 24 Gy (n = 4), and 30 Gy (n = 3), and 207 lesions were treated. Nine patients (69%) had acute toxicity: grade 1 (n = 6, 46%), grade 2 (n = 2, 15%; n = 1 pneumonitis and n = 1 fatigue), and grade 3 (n = 1, 7.7% neutropenia). There were no grade 4 or 5 toxicities. Mean ± SD quality of life (Functional Assessment of Cancer Therapy - General and European Quality of Life 5 Dimension 5 Level health state) was 80.4 ± 21.9 and 77.4 ± 20.9 at baseline versus 76.4 ± 21.8 and 68.0 ± 24.2 at 6-week follow-up, respectively (p = .009 and p = .055, respectively). With a median follow-up of 8.7 months posttreatment (IQR, 2.4-24 months), 8 of 13 patients had disease progression (62%). The median and 12-month progression-free survival were 3.6 months and 11.3%, respectively. The median and 12-month overall survival were 13.8 months and 62%, respectively. In this phase 1 trial, SABR therapy for polymetastatic disease was technically feasible with acceptable acute toxicity at dose levels up to 30 Gy (6 Gy weekly × 5). DLT was not observed.

TET2 regulates extranodal NK/T cell lymphoma progression through regulation of DNA methylation.

The biological role of Ten-11 translocation 2 (TET2) and the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the development of extra-nodal natural killer/T-cell lymphoma (ENKTL) remains unclear. The level of 5mC and 5hmC was detected in 112 cases of ENKTL tissue specimens by immunohistochemical (IHC) staining. Subsequently, TET2 knockdown and the overexpression cell models were constructed in ENKTL cell lines. Biochemical analyses were used to assess proliferation, apoptosis, cell cycle and monoclonal formation in cells treated or untreated with L-Ascorbic acid sodium salt (LAASS). Dot-Blots were used to detect levels of genome 5mC and 5hmC. Additionally, the ILLUMINA 850k methylation chip was used to analyze the changes of TET2 regulatory genes. RNA-Seq was used to profile differentially expressed genes regulated by TET2. The global level of 5hmC was significantly decreased, while 5mC was highly expressed in ENKTL tissue. TET2 protein expression was negatively correlated with the ratio of 5mC/5hmC (p<0.0001). The 5mC/5hmC status were related to the site of disease, clinical stage, PINK score and Ki-67 index, as well as the 5-year OS. TET2 knockdown prolonged the DNA synthesis period, increased the cloning ability of tumor cells, increased the level of 5mC and decreased the level of 5hmC in ENKTL cells. While overexpression of TET2 presented the opposite effect. Furthermore, treatment of ENKTL cells with LAASS significantly induced ENKTL cell apoptosis. These results suggest that TET2 plays an important role in ENKTL development via regulation of 5mC and 5hmC and may serve as a novel therapeutic target for ENKTL.

Impact of Primary Disease Site of Involvement by Early-Stage Follicular Lymphoma on Patient Outcomes

IntroductionFollicular lymphoma is a common non-Hodgkin lymphoma that can start in a diverse array of tissues throughout the body. While the majority of patients may be able to live many years with this disease, cure remains very difficult to achieve. ObjectiveWe sought to investigate the impact of follicular lymphoma primary disease site in early-stage disease on patient outcomes using a large national database. MethodsBaseline demographic and disease data for patients diagnosed with follicular lymphoma from 2000-2015 was identified and extracted from the NCI Surveillance, Epidemiology, and End Results (SEER) database. Primary disease sites were grouped into one of two cohorts: nodal disease (lymph nodes and spleen) and extranodal disease (everything else). Analysis was performed using summary statistics, Kaplan-Meier method, and Cox-proportional hazards models for univariate and multivariate analysis. ResultsA total of 13,400 patients were included in the final analysis and the majority were non-Hispanic white (81%), with stage I (63%), and nodal FL (79%). Median overall survival for nodal disease was 15.1 years [95% CI (14.6-15.6)] while median overall survival for extranodal disease was 15.8 years [95% CI (14.9-16.3)]. Overall survival was slightly better for patients with extranodal disease [HR = 0.89, 95% CI (0.84-0.96); p-value = 0.00012]. This finding remained consistent after controlling for age and race [HR = 0.84, 95% CI (0.79-0.90); p-value <0.0001]. ConclusionsThe primary site of involvement by early-stage follicular lymphoma may have an impact on patient outcomes and warrants further investigation.

Palliating hematologic oncologic emergencies with radiation in the age of targeted systemic therapies: three illustrative cases.

Hematologic oncologic emergencies with an urgent indication for radiation are a relatively routine occurrence for the radiation oncologist. As patients are living longer and have multiple treatment options for their relapsed or refractory diseases, it is important that palliative treatments avoid precluding patients from or delaying next-line potentially curative treatments wherever possible. We highlight the following experiences from our clinical practice: newly diagnosed plasma cell disease causing cord compression; life threatening cutaneous lymphoma with tumors covering the majority of the body surface area; and relapsed/refractory diffuse large B-cell lymphoma (DLBCL) requiring bridging radiation to a mass impinging on the brachial plexus combined with chimeric antigen receptor (CAR)-T cell therapy. In each case, urgent palliative radiation was utilized, but the approaches were nuanced, with careful consideration of subsequent potential therapies and how the current course of radiation should be tailored for the best interplay with the overall treatment course and trajectory of the disease. With the rapid development of new therapies, it can be difficult to stay up to date on the most recent practice guidelines. Drawing on hematologic-specific guidelines, such as those provided by the International Lymphoma Radiation Oncology Group, and disease site experts can aid in ensuring patients are appropriately palliated and eligible for future therapies.