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Investigative Ophthalmology & Visual... Jun 2024Regression of retinoblastoma vitreous seeds (VS) during intravitreal chemotherapy can be delayed, resulting in supernumerary injections. Similarly, VS relapse may not be...
PURPOSE
Regression of retinoblastoma vitreous seeds (VS) during intravitreal chemotherapy can be delayed, resulting in supernumerary injections. Similarly, VS relapse may not be clinically evident at first. A predictive biomarker of tumor regression and relapse could help guide real-time clinical decision making. Retinoblastoma is an oxygen-sensitive tumor; paradoxically, VS survive in the hypoxic vitreous. We hypothesized that VS elaborate pro-angiogenic cytokines. The purpose was to determine if pro-angiogenic cytokine signatures from aqueous humor could serve as a biomarker of VS response to treatment.
METHODS
Multiplex ELISA was performed on aqueous from rabbit eyes with human retinoblastoma VS xenografts to identify expressed proangiogenic cytokines and changes in aqueous cytokine levels during intravitreal treatment were determined. Confirmatory RNAscope in situ hybridization for VEGF-A was performed on human retinoblastoma tumor sections and VS xenografts from rabbits. For human eyes undergoing intravitreal chemotherapy, serial aqueous VEGF-A levels measured via VEGF-A-specific ELISA were compared to clinical response.
RESULTS
VEGF-A was highly expressed in human retinoblastoma VS in the xenograft model, and was the only proangiogenic cytokine that correlated with VS disease burden. In rabbits, aqueous VEGF-A levels decreased in response to therapy, consistent with quantitative VS reduction. In patients, aqueous VEGF-A levels associated with clinical changes in disease burden (regression, stability, or relapse), with changes in VEGF-A levels correlating with clinical response.
CONCLUSIONS
Aqueous VEGF-A levels correlate with extent of retinoblastoma VS, suggesting that aqueous VEGF-A may serve as a predictive molecular biomarker of treatment response.
Topics: Retinoblastoma; Animals; Retinal Neoplasms; Vascular Endothelial Growth Factor A; Aqueous Humor; Humans; Vitreous Body; Rabbits; Biomarkers, Tumor; Enzyme-Linked Immunosorbent Assay; Liquid Biopsy; Intravitreal Injections; Neoplasm Seeding; Female; Angiogenesis Inhibitors; Cytokines
PubMed: 38861274
DOI: 10.1167/iovs.65.6.18 -
Infection Prevention in Practice Sep 2024Gastroenteritis accounts for about 10% of the deaths among children, especially in immunocompromised children. Few studies on the prevalence of gastrointestinal...
BACKGROUND
Gastroenteritis accounts for about 10% of the deaths among children, especially in immunocompromised children. Few studies on the prevalence of gastrointestinal infections caused by RNA viruses have been done in Iran. The aim of the study was to evaluate the detection of RNA viruses causing diarrhoea using a multiplex PCR.
METHODS
Stool samples were collected from 130 paediatric patients with diarrhoea who had acute lymphocytic leukaemia, non-Hodgkin lymphoma, and retinoblastoma. After RNA extraction and synthesis of cDNA, multiplex PCR was done to evaluate the presence of rotavirus, norovirus, astrovirus, and enterovirus.
RESULTS
There were 9 (6.9%), 7 (5.4%), 3 (2.3%), and 6 (4.6%) cases of rotavirus, norovirus, astrovirus, and enterovirus detected, respectively. One case of co-infection with astrovirus and norovirus was observed.
CONCLUSIONS
This is the first report from Iran which identified the presence of common RNA viruses causing diarrhoea in immunocompromised children. Increased awareness of these viruses will enable healthcare professionals to improve strategies and policies to control spread and infection caused by these viruses.
PubMed: 38855735
DOI: 10.1016/j.infpip.2024.100370 -
Translational Andrology and Urology May 2024Small cell neuroendocrine prostate cancer (SCNC) is a rare aggressive type of neuroendocrine prostate cancer (NEPC) characterized by aggressive clinical course and lack...
BACKGROUND
Small cell neuroendocrine prostate cancer (SCNC) is a rare aggressive type of neuroendocrine prostate cancer (NEPC) characterized by aggressive clinical course and lack of response to hormone therapy.
CASE DESCRIPTION
We present a case report of a 60-year-old man diagnosed with a histologically confirmed primary metastatic (bone, lymph nodes and visceral) SCNC with small components of an adenocarcinoma with clinical symptoms mimicking an acute prostatitis. Of note, serum based neuroendocrine markers (carcinoembryonic antigen, chromogranin A) were negative and the patient had a prostate-specific antigen (PSA) elevation. Genetic testing of tumor tissue revealed breast cancer gene 2 () copy number loss and a retinoblastoma gene () mutation reflecting again the aggressiveness of the disease. Germline testing for the copy number loss was unremarkable. After 6 cycles of carboplatin and etoposide in combination with androgen deprivation therapy (ADT) the Eastern Cooperative Oncology Group (ECOG) performance status has improved from 3 to 0, in addition the patient was free of pain. In line with clinical improvement, both prostate-specific membrane antigen (PSMA) and fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) revealed a significant reduction of metastatic load. Currently, the patient is treated with ADT plus apalutamide.
CONCLUSIONS
We demonstrate for the first time a case of a primary metastatic SCNC with adenocarcinoma components successfully treated by the combination of platinum-based chemotherapy plus hormonal therapy. In addition, we provide a literature overview on management of SCNC as there is no standard treatment established for this disease.
PubMed: 38855597
DOI: 10.21037/tau-23-541 -
Translational Lung Cancer Research May 2024Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6...
CDK4/6 inhibitor abemaciclib combined with low-dose radiotherapy enhances the anti-tumor immune response to PD-1 blockade by inflaming the tumor microenvironment in Rb-deficient small cell lung cancer.
BACKGROUND
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6 substrate retinoblastoma (Rb) protein, while the anti-tumor effect of CDK4/6 inhibitors on Rb-deficient tumors is not clear. Most small cell lung cancers (SCLCs) are Rb-deficient and show very modest response to immune checkpoint blockade (ICB) despite recent advances in the use of immunotherapy. Here, we aimed to investigate the direct effect of CDK4/6 inhibition on SCLC cells and determine its efficacy in combination therapy for SCLC.
METHODS
The immediate impact of CDK4/6 inhibitor abemaciclib on cell cycle, cell viability and apoptosis in four SCLC cell lines was initially checked. To explore the effect of abemaciclib on double-strand DNA (ds-DNA) damage induction and the combination impact of abemaciclib coupled with radiotherapy (RT), western blot, immunofluorescence (IF) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. An Rb-deficient immunocompetent murine SCLC model was established to evaluate efficacy of abemaciclib in combination therapy. Histological staining, flow cytometry analysis and RNA sequencing were performed to analyze alteration of infiltrating immune cells in tumor microenvironment (TME).
RESULTS
Here, we demonstrated that abemaciclib induced increased ds-DNA damage in Rb-deficient SCLC cells. Combination of abemaciclib and RT induced more cytosolic ds-DNA, and activated the STING pathway synergistically. We further showed that combining low doses of abemaciclib with low-dose RT (LDRT) plus anti-programmed cell death protein-1 (anti-PD-1) antibody substantially potentiated CD8 T cell infiltration and significantly inhibited tumor growth and prolonged survival in an Rb-deficient immunocompetent murine SCLC model.
CONCLUSIONS
Our results define previously uncertain DNA damage-inducing properties of CDK4/6 inhibitor abemaciclib in Rb-deficient SCLCs, and demonstrate that low doses of abemaciclib combined with LDRT inflame the TME and enhance the efficacy of anti-PD-1 immunotherapy in SCLC model, which represents a potential novel therapeutic strategy for SCLC.
PubMed: 38854937
DOI: 10.21037/tlcr-24-33 -
Canadian Journal of Ophthalmology.... Jun 2024
PubMed: 38848766
DOI: 10.1016/j.jcjo.2024.04.012 -
Advances in Ophthalmology Practice and... 2024Intraocular malignant tumors represent a severe disease that threatens vision as well as life. To better extend the life of the patient, preserve visual function, and... (Review)
Review
BACKGROUND
Intraocular malignant tumors represent a severe disease that threatens vision as well as life. To better extend the life of the patient, preserve visual function, and maintain ocular aesthetics, selecting the appropriate timing and methods of treatment becomes crucial.
MAIN TEXT
With the continuous advancement of medical technology, the techniques and methods for treating intraocular malignant tumors are constantly evolving. While surgery was once considered the optimal method to prolong patient survival and prevent local recurrence, the discovery and application of various treatments such as radiotherapy, laser therapy, chemotherapy, cryotherapy, and monoclonal antibodies have led to a greater diversity of treatment options. This diversity offers more possibilities to develop personalized treatment plans, and thereby maximize patient benefit. This article reviews the various treatment methods for intraocular malignant tumors, including indications for treatment, outcomes, and potential complications.
CONCLUSIONS
Differentiating small intraocular malignant tumors from pigmented lesions is challenging, and ongoing monitoring with regular follow-up is required. Small to medium-sized tumors can be treated with radiotherapy combined with transpupillary thermotherapy. Depending on the tumor's distance from the optic disc, surgery with partial resection may be considered for distant tumors, while proximal tumors may require complete enucleation. Systemic chemotherapy has been widely applied to patients with retinal tumors, lymphomas, and intraocular metastatic cancers, but has limited efficacy in patients with choroidal melanoma. Antagonists of Vascular Endothelial Growth Factor (Anti-VEGF) drugs can improve patient vision and quality of life, while the efficacy of immunotherapy and molecular targeted therapy is still under research.
PubMed: 38846623
DOI: 10.1016/j.aopr.2024.03.005 -
Acta Medica Philippina 2024Retinoblastoma is the most common intraocular cancer in childhood in the Philippines. Most data though on demographics, clinical profile, treatment options, and outcomes...
BACKGROUND
Retinoblastoma is the most common intraocular cancer in childhood in the Philippines. Most data though on demographics, clinical profile, treatment options, and outcomes in the country are from the National Capital Region.
OBJECTIVES
This study aimed to describe the demographics, clinical profile, treatment done, and outcomes of retinoblastoma patients seen in a public tertiary referral center in Davao from 2011-2020 to make available literature more representative of the status of retinoblastoma in the Philippines.
METHODS
An analytical cross-sectional study was conducted using the records of retinoblastoma patients seen in a tertiary government hospital located in Davao Region from January 2011 to December 2020.
RESULTS
There were 157 patients included in the analysis. Seventy-three (46%) were female with 44% coming from the Davao Region. One hundred seven (69%) patients had unilateral disease. Median age at initial consultation for patients with unilateral disease was significantly older than those with bilateral disease (p<0.003). Tumors were extraocular in 82 (40%) eyes. In the intraocular group, 36% of the eyes belonged to International Classification of Retinoblastoma (ICRB) Groups D and E. Enucleation was the most commonly performed treatment. Survival rate was 28%.This is the first report to provide epidemiologic and clinical data on retinoblastoma in the literature, including survival data, from Mindanao. Advanced stages and extraocular cases of retinoblastoma remain high. Delay of consultation contributed to the prognosis and clinical outcome of the disease.
CONCLUSION
Advanced stages and extraocular cases of retinoblastoma remain significantly high in the country, even in Mindanao.
PubMed: 38846169
DOI: 10.47895/amp.vi0.6754 -
Nature Medicine Jun 2024Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously...
Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 .
PubMed: 38844794
DOI: 10.1038/s41591-024-03025-3 -
European Journal of Cancer Prevention :... May 2024This systematic review aims to synthesize the available literature to determine the association between birthweight and the risk of nonneurological childhood cancers.
OBJECTIVES
This systematic review aims to synthesize the available literature to determine the association between birthweight and the risk of nonneurological childhood cancers.
METHODS
We conducted a systematic search of PubMed, Web of Science, and Scopus databases up to May 2023 to identify observational studies. Heterogeneity between studies was evaluated using the I2 statistics. Publication bias was assessed using Begg and Egger tests. We calculated the odds ratio (OR) or risk ratio (RR) with a 95% confidence interval (CI) using a random-effects model.
RESULTS
Of 11 034 studies retrieved from the search, 56 studies (including 10 568 091 participants) were eligible. The ORs (95% CI) of low (<2500 g) versus normal birthweight (2500-4000 g) and childhood cancers were as follows: leukemia, 0.92 (0.77-1.11); acute lymphoblastic leukemia, 0.82 (0.72-0.94); acute myeloid leukemia, 0.98 (0.77-1.24); lymphoma, 0.99 (0.47-2.10); Hodgkin, 0.79 (0.61-1.03); non-Hodgkin, 0.85 (0.60-1.20); neuroblastoma, 1.34 (1.14-1.58); retinoblastoma, 0.95 (0.68-1.32); rhabdomyosarcoma, 0.86 (0.61-1.20); embryonal, 0.97 (0.66-1.43); alveolar, 1.92 (0.43-8.51); and Wilms tumor, 1.01 (0.83-1.24). The ORs (95% CI) of high (>4000 g) versus normal birthweight and childhood cancers were as follows: leukemia, 1.30 (1.18-1.42); acute lymphoblastic leukemia, 1.27 (1.16-1.39); acute myeloid leukemia, 1.13 (0.98-1.30); lymphoma, 1.69 (0.72-3.94); Hodgkin, 1.22 (1.02-1.46); non-Hodgkin, 1.22 (0.80-1.86); neuroblastoma, 1.20 (1.02-1.41); retinoblastoma, 1.17 (0.93-1.48); rhabdomyosarcoma, 1.07 (0.90-1.27); embryonal, 1.22 (1.00-1.49); alveolar, 1.02 (0.46-2.27); and Wilms tumor, 1.49 (1.34-1.67).
CONCLUSION
This meta-analysis identified high birth weight as a potential risk factor for some childhood cancers, while low birth weight might be protective against a few.
PubMed: 38837193
DOI: 10.1097/CEJ.0000000000000894 -
Skin Appendage Disorders Jun 2024Retinoblastoma is the most common intraocular tumor in the pediatric population. Its main therapeutic objectives are to avoid fatal outcomes and preserve vision as much... (Review)
Review
BACKGROUND
Retinoblastoma is the most common intraocular tumor in the pediatric population. Its main therapeutic objectives are to avoid fatal outcomes and preserve vision as much as possible. Intra-arterial chemotherapy (IAC) improves drug delivery and reduces possible systemic adverse effects. This modality allows direct administration of chemotherapeutic agents to intraocular malignancies via the ophthalmic artery (OA), proving to be a feasible and effective method for globe salvage. Most side effects of IAC are local, including eyelash loss of the nasal portion of the eyelid.
SUMMARY
We performed a comprehensive review to analyze data regarding ciliary madarosis in patients diagnosed with retinoblastoma treated with IAC. We describe 9 studies with a total of 637 eyes with retinoblastoma that underwent IAC, of which 45 cases presented madarosis. In chemotherapy-induced alopecia, there is hair shaft thinning and breakage. On trichoscopy, the remaining end of the fractured hair will be observed as black dots. Differential diagnoses must include alopecia areata and trichotillomania.
KEY MESSAGES
Ciliary madarosis secondary to IAC, although transitional, may cause discomfort in patients and family members. Physical examination, as well as a trichoscopic evaluation of the affected area, can help in reaching a prompt diagnosis and prognosis for this particular alopecia.
PubMed: 38835713
DOI: 10.1159/000535826