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Pediatrics Nov 2022We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment of Wilms tumor.
OBJECTIVES
We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment of Wilms tumor.
METHODS
Survivors of Wilms tumor (n = 280) participating in the St. Jude Lifetime Cohort, a retrospective study with prospective follow-up of individuals treated for childhood cancer at St. Jude Children's Research Hospital, were clinically evaluated and compared to age and sex-matched controls (n = 625). Health conditions were graded per a modified version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Standardized neurocognitive testing was graded by using age-adjusted z-scores. Impaired physical function was defined by age- and sex-matched z-scores >1.5 SD below controls. Modified Poisson regression was used to compare the prevalence of conditions and multivariable logistic regression to examine treatment associations.
RESULTS
Median age at evaluation was similar between survivors and controls (30.5 years [9.0-58.0] and 31.0 [12.0-70.0]). Therapies included nephrectomy (100%), vincristine (99.3%), dactinomycin (97.9%), doxorubicin (66.8%), and abdominal (59.3%) and/or chest radiation (25.0%). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7-13.8) grade 1-4 and 7.5 (CI: 6.7-8.2) grade 2 to 4 health conditions, compared to 4.2 (CI: 3.9-4.6) and 2.3 (CI: 2.1-2.5), respectively, among controls. Grade 2 to 4 endocrine (53.9%), cardiovascular (26.4%), pulmonary (18.2%), neurologic (8.6%), neoplastic (7.9%), and kidney (7.2%) conditions were most prevalent. Survivors exhibited neurocognitive and physical performance impairments.
CONCLUSIONS
Wilms tumor survivors experience a threefold higher burden of chronic health conditions compared to controls and late neurocognitive and physical function deficits. Individualized clinical management, counseling, and surveillance may improve long-term health maintenance.
Topics: Child; Humans; Adult; Retrospective Studies; Prospective Studies; Survivors; Wilms Tumor; Chronic Disease; Kidney Neoplasms; Outcome Assessment, Health Care
PubMed: 36300342
DOI: 10.1542/peds.2022-056918 -
Journal of the Formosan Medical... Aug 2023The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC).
PURPOSE
The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC).
METHODS
Firstly, we used qRT-PCR and Western blot to compare the difference in the expression of ZC3H13 between normal thyroid epithelial cells and PTC cell lines. Then, ZC3H13 overexpression/knockout thyroid cancer cells were constructed by lentivirus transfection, and the effects of overexpression of ZC3H13 on the proliferation, migration and invasion of PTC cells were detected by CCK8 and transwell experiments. Lastly, MeRIP-qPCR, RIP and o Actinomycin D were used to verify that ZC3H13 regulated the expression of downstream target gene IQGAP1 through m6A modification.
RESULTS
ZC3H13 expression was decreased in PTC cell lines BCPAP, KTC-1, k1, HTH83, and TPC-1. Proliferation, invasion, and migration of PTC cells were inhibited by overexpressed ZC3H13 but increased by knockdown of ZC3H13. IQGAP1 expression was suppressed by ZC3H13 overexpression but enhanced by ZC3H13 knockdown. In ZC3H13-overexpressed PTC cells, the m6A level of IQGAP1 mRNA was increased, and the IQGAP1 mRNA expression was decreased with the increasing time of Actinomycin D treatment. YTHDF2 enriched more IQGAP1 mRNA than IgG and knockdown of YTHDF2 reversed the effect of ZC3H13 overexpression on IQGAP1 mRNA stability. The xenograft tumor experiment in nude mice confirmed that the overexpression of ZC3H13 inhibited tumor growth, while overexpression of IQGAP1 could reverse the inhibitory effect of ZC3H13 overexpression on tumor growth.
CONCLUSION
ZC3H13 mediates IQGAP1 mRNA degradation by promoting m6A modification of IQGAP1 mRNA, this provides a prospective therapeutic target for PTC.
Topics: Mice; Animals; Humans; Thyroid Cancer, Papillary; MicroRNAs; Mice, Nude; Dactinomycin; Cell Line, Tumor; Cell Proliferation; Neoplasm Invasiveness; Cell Movement; Thyroid Neoplasms; RNA, Messenger; Gene Expression Regulation, Neoplastic; Nuclear Proteins; RNA-Binding Proteins
PubMed: 36739231
DOI: 10.1016/j.jfma.2022.12.019 -
Cancer Jan 2022The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective.
METHODS
A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs.
RESULTS
Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices.
CONCLUSIONS
Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions.
LAY SUMMARY
Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cost-Benefit Analysis; Cyclophosphamide; Dactinomycin; Drug Costs; Humans; Rhabdomyosarcoma; Vincristine
PubMed: 34623638
DOI: 10.1002/cncr.33917 -
Journal of Clinical Oncology : Official... Nov 2022Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.
PATIENTS AND METHODS
In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible.
RESULTS
MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% ( < .0001) and 3-year OS 60.0% versus 26.0% ( < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance.
CONCLUSION
Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.
Topics: Child; Humans; Disease-Free Survival; Antineoplastic Combined Chemotherapy Protocols; Rhabdomyosarcoma; Sarcoma; Ifosfamide; Vincristine; Cyclophosphamide; Dactinomycin; Doxorubicin; Neoplasms, Second Primary
PubMed: 35709412
DOI: 10.1200/JCO.21.02981 -
Leukemia Sep 2021Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML...
Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.
Topics: Aged; Antibiotics, Antineoplastic; Cell Nucleolus; Dactinomycin; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Nuclear Proteins; Nucleophosmin; Pilot Projects; Prognosis; Remission Induction; Salvage Therapy
PubMed: 33654209
DOI: 10.1038/s41375-021-01192-7 -
Proceedings of the National Academy of... Aug 2021Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only...
Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor-induced apoptosis on the mitochondria.
Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoptosis; Cell Line; Cyclosporine; Dactinomycin; Doxorubicin; Enzyme Inhibitors; Fas Ligand Protein; Gene Deletion; Gene Expression Regulation, Enzymologic; Hexokinase; Humans; Mitochondria; TNF-Related Apoptosis-Inducing Ligand; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 34385311
DOI: 10.1073/pnas.2021175118 -
Clinical Case Reports Oct 2023Choriocarcinoma of the fallopian tube is extremely rare and highly susceptible to early metastasis. Clinical manifestations of ectopic pregnancy and choriocarcinoma are...
KEY CLINICAL MESSAGE
Choriocarcinoma of the fallopian tube is extremely rare and highly susceptible to early metastasis. Clinical manifestations of ectopic pregnancy and choriocarcinoma are the same, and all patients with ectopic pregnancy should be evaluated for choriocarcinoma based on histopathological findings. Adjuvant chemotherapy (after surgery) is the proposed treatment for tubal choriocarcinoma.
ABSTRACT
Choriocarcinoma is a malignant epithelial tumor of the chorionic villi that often manifests after a normal or molar pregnancy. The primary tubal choriocarcinoma associated with ectopic pregnancy is extremely rare and can be misdiagnosed as an ectopic pregnancy since symptoms including vaginal bleeding, amenorrhea, elevated beta-human chorionic gonadotropin (BHCG) levels, and pelvic pain are shared. A 34-year-old G4P3003 woman presented with a one-week history of vaginal bleeding and right lower abdominal pain, which had intensified a day before admission. Clinical and paraclinical examinations pointed to a ruptured tubal pregnancy; hence, an emergency laparotomy was performed, and a right salpingectomy was carried out on the patient. However, a nonsignificant decline in BHCG level was observed, and histological examination revealed tubal choriocarcinoma; hence, a metastasis workup was carried out, yet no metastasis was detected. Six sessions of chemotherapy consisting of Etoposide, Methotrexate, Dactinomycin, Cyclophosphamide, and Vincristine (EMA-CO) were administered without complication, in such a way that the BHCG level normalized after three sessions of chemotherapy. Evaluations after 1 year from the completion of chemotherapy revealed that the patient had no subsequent problems. Choriocarcinoma of the fallopian tube is extremely rare and highly susceptible to early metastasis. Clinical manifestations of ectopic pregnancy and choriocarcinoma are the same, and all patients with ectopic pregnancy should be evaluated for choriocarcinoma based on histopathological findings. Metastasis workup should be considered for all individuals with choriocarcinoma. Adjuvant chemotherapy (after surgery) is the proposed treatment for tubal choriocarcinoma.
PubMed: 37780932
DOI: 10.1002/ccr3.7977 -
Frontiers in Oncology 2024Endoplasmic reticulum (ER) stress arises from the accumulation of misfolded or unfolded proteins within the cell and is intricately linked to the initiation and...
BACKGROUND
Endoplasmic reticulum (ER) stress arises from the accumulation of misfolded or unfolded proteins within the cell and is intricately linked to the initiation and progression of various tumors and their therapeutic strategies. However, the precise role of ER stress in uterine corpus endometrial cancer (UCEC) remains unclear.
METHODS
Data on patients with UCEC and control subjects were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Using differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA), we identified pivotal differentially expressed ER stress-related genes (DEERGs). Further validation of the significance of these genes in UCEC was achieved through consensus clustering and bioinformatic analyses. Using Cox regression analysis and several machine learning algorithms (least absolute shrinkage and selection operator [LASSO], eXtreme Gradient Boosting [XGBoost], support vector machine recursive feature elimination [SVM-RFE], and Random Forest), hub DEERGs associated with patient prognosis were effectively identified. Based on the four identified hub genes, a prognostic model and nomogram were constructed. Additionally, a drug sensitivity analysis and validation experiments were performed.
RESULTS
A total of 94 DEERGs were identified in patients with UCEC and healthy controls. Consensus clustering analysis revealed significant differences in prognosis, typical immune checkpoints, and tumor microenvironments between the subtypes. Using Cox regression analysis and machine learning, four hub DEERGs, MYBL2, RADX, RUSC2, and CYP46A1, were identified to construct a prognostic model. The reliability of the model was validated using receiver operating characteristic (ROC) curves. Decision curve analysis (DCA) demonstrated the superior predictive ability of the nomogram in terms of 3- and 5-year survival, compared with that of other clinical indicators. Drug sensitivity analysis revealed increased sensitivity to dactinomycin, docetaxel, selumetinib, and trametinib in the low-risk group. The expressions of RADX, RUSC2, and CYP46A1 were downregulated, whereas that of MYBL2 was upregulated in UCEC tissues, as demonstrated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence assays.
CONCLUSION
This study developed a stable and accurate prognostic model based on multiple bioinformatics analyses, which can be used to assess the prognosis of UCEC. This model may contribute to future research on the risk stratification of patients with UCEC and the formulation of novel treatment strategies.
PubMed: 38725627
DOI: 10.3389/fonc.2024.1362891 -
European Journal of Cancer (Oxford,... Sep 2019In the fifth National Wilms Tumor Study (NWTS-5), the 4-year event-free survival (EFS) and overall survival (OS) estimates for 29 patients with stage I focal (n = 10)... (Comparative Study)
Comparative Study
BACKGROUND
In the fifth National Wilms Tumor Study (NWTS-5), the 4-year event-free survival (EFS) and overall survival (OS) estimates for 29 patients with stage I focal (n = 10) or diffuse (n = 19) anaplastic Wilms' tumour (AWT) treated with vincristine and dactinomycin without flank radiation were 69.5% and 82.6%, respectively. The Children's Oncology Group AREN0321 study evaluated whether adding doxorubicin and flank radiation improves survival for these patients.
PATIENTS AND METHODS
Tumour histology and stage were confirmed by real-time central pathology, surgery and radiology review. The patients received 25 weeks of vincristine, dactinomycin and doxorubicin (cumulative dose 150 mg/m) with flank radiation (1080 cGy). We retrospectively analysed outcomes of all patients with stage I AWT enrolled in NWTSs 1-5 and AREN0321 with respect to treatment regimens.
RESULTS
Eighteen patients with stage I AWT (8 focal and 10 diffuse) were enrolled on AREN0321. With a median follow-up of 4.6 years, the 4-year EFS and OS were 100%. One patient with diffuse AWT had pulmonary relapse 4.12 years after diagnosis. In the 112 patients with stage I AWT treated in NWTSs 1-5 and AREN0321, the EFS was significantly improved with doxorubicin treatment (p = 0.01; 4-year EFS: 97.2% [95% confidence interval {CI}: 91.3-100] vs. 77.5% [95% CI: 67.6-87.4]) but not by flank radiation (p = 0.15).
CONCLUSIONS
Treatment of stage I AWT with vincristine, dactinomycin, doxorubicin and flank radiation in AREN0321 yielded excellent survival outcomes. Retrospective analysis of AREN0321 and NWTS patients suggests that doxorubicin had a greater contribution to the excellent outcomes than radiation.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Child; Child, Preschool; Dactinomycin; Disease Progression; Doxorubicin; Female; Humans; Infant; Kidney Neoplasms; Male; Neoplasm Staging; Nephrectomy; Progression-Free Survival; Radiotherapy, Adjuvant; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; United States; Vincristine; Wilms Tumor
PubMed: 31325873
DOI: 10.1016/j.ejca.2019.05.033 -
Indian Journal of Cancer 2022Gestational trophoblastic neoplasia (GTN) are a spectrum of tumors that develop from placental tissue. We aimed to evaluate the management and treatment outcome of GTN.
BACKGROUND
Gestational trophoblastic neoplasia (GTN) are a spectrum of tumors that develop from placental tissue. We aimed to evaluate the management and treatment outcome of GTN.
METHODS
Patients diagnosed with GTN presented to Kasr Alainy Center of Clinical Oncology between 2008 and 2017 were included in this study. Patients were assigned to low or high-risk according to the World Health Organization (WHO) scoring system. All data were tabulated and statistically studied by descriptive analysis; comparison between the two groups was done using student t-test for continuous data and Chi-square test for categorical data.
RESULTS
A total of 111 patients were studied; the majority of them had WHO low-risk score. In low-risk group, the overall response rate to methotrexate-folinic acid (MTX- FA) or actinomycin D (ActD) was 48.5%, comparable response rate observed between MTX and ActD was 48.2% vs 50%, respectively. Those who received MTX-FA 8-day regimen had higher response rate compared to a weekly schedule, however, no statistical significant difference was observed (51.6% vs 44.4%, respectively, P = 0.586), all low-risk patients who failed MTX or ActD achieved complete remission (CR) with subsequent chemotherapy. Patients with WHO score 5-6 had a significantly lower CR rate compared to patients with scores <5, (28% and 60%, respectively; P = 0.01). Five-years overall survival was significantly lower in high-risk than low-risk patients (79.3% vs 100%, respectively, P = <0.001).
CONCLUSION
Low-risk patients have a survival rate of 100% even if they did not respond to first-line chemotherapy, MTX-FA 8-day regimen seems to be more effective than MTX weekly regimen.
Topics: Dactinomycin; Egypt; Female; Gestational Trophoblastic Disease; Humans; Methotrexate; Placenta; Pregnancy; Retrospective Studies; Risk Factors; Treatment Outcome
PubMed: 33402570
DOI: 10.4103/ijc.IJC_551_19