•HNSCC xenografts depict heterogeneous expression of hypoxia gene signatures which weakly correlate with the histologic surrogate for hypoxia pimonidazole.•Untreated and radiochemotherapy (with and ...without nimorazole)-treated responder and non-responder tumor models depict specific differential expression and methylation profiles.•Nimorazole non-responder models exhibit increased expression of genes associated to retinol metabolism and xenobiotic metabolic process.•A subset of 15 genes upregulated in untreated nimorazole non-responder models showed prognostic value also in HNSCC patients, defining a high-risk group for loco-regional failure and overall survival after primary radiochemotherapy.
Hypoxia remains a challenge for the therapeutic management of head and neck squamous cell carcinoma (HNSCC). The combination of radiotherapy with nimorazole has shown treatment benefit in HNSCC, but the precise underlying molecular mechanisms remain unclear.
To assess and to characterize the transcriptomic/epigenetic landscape of HNSCC tumor models showing differential therapeutic response to fractionated radiochemotherapy (RCTx) combined with nimorazole.
Bulk RNA-sequencing and DNA methylation experiments were conducted using untreated and treated HNSCC xenografts after 10 fractions of RCTx with and without nimorazole. These tumor models (FaDu, SAS, Cal33, SAT and UT-SCC-45) previously showed a heterogeneous response to RCTx with nimorazole. The prognostic impact of candidate genes was assessed using clinical and gene expression data from HNSCC patients treated with primary RCTx within the DKTK-ROG.
Nimorazole responder and non-responder tumor models showed no differences in hypoxia gene signatures However, non-responder models showed upregulation of metabolic pathways. From that, a subset of 15 differentially expressed genes stratified HNSCC patients into low and high-risk groups with distinct outcome.
In the present study, we found that nimorazole non-responder models were characterized by upregulation of genes involved in Retinol metabolism and xenobiotic metabolic process pathways, which might contribute to identify mechanisms of resistance to nitroimidazole compounds and potentially expand the repertoire of therapeutic options to treat HNSCC.
•Epigenetic changes like methylation can occur during cell division without altering the DNA molecule sequence.•Radiochemotherapy can significantly change methylation patterns.•Evaluation of ...methylation patterns might serve as a valuable biomarker to predict response to radiochemotherapy.•Monitoring DNA methylation patterns during the treatment can be a potential prognostic and target therapy tool in cancer patients.
This study aims to investigate cell-free DNA (cfDNA) methylation of genes involved in some immune system targets as biomarkers of radioresistance in patients with non-metastatic rectal cancer.
Gene expression (GSE68204, GPL6480, and GSE15781) and DNA methylation profiles (GSE75548 and GSE139404) of rectal cancer patients were obtained from the Gene Expression Omnibus (GEO) database. GEO2R and FunRich software were first used to identify genes with significant expression differences. Enricher softwer was then used to analyze Gene Ontology and detect pathway enrichment of hub genes. Blood samples were then taken from 43 rectal cancer patients. After cfDNA extraction from samples, it was treated with bisulfite and analyzed by methylation-specific PCR.
1088 genes with high and 629 with low expression were identified by GEO2R and FunRich software. A total of five high-expression hub genes, including CDH24, FGF18, CCND1, IFITM1, UBE2V1, and three low-expression hub genes, including CBLN2, VIPR2, and IRF4, were identified from UALCAN and DNMIVD databases. Methylation-specific PCR indicated a significant difference in hub gene methylation between cancerous and non-cancerous individuals. Radiochemotherapy significantly affected hub gene methylation. There was a considerable difference in the methylation rate of hub genes between patients who responded to radiochemotherapy and those who did not.
Evaluating gene methylation patterns might be an appropriate diagnostic tool to predict radiochemotherapy response and develop targeted therapeutic agents.
Objective:
The aim of this study was to pool data from randomized controlled trials (RCT) limited to
resectable
pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy ...impacts on disease-free survival (DFS) and surgical outcome.
Summary Background Data:
Few underpowered studies have suggested benefits from neoadjuvant chemo (± radiation) for strictly resectable PDAC without offering conclusive recommendations.
Methods:
Three RCTs were identified comparing neoadjuvant chemo (± radio) therapy
vs.
upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards.
Results:
A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only
hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4–0.9 (
P
= 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35–0.9,
P
= 0.045). Although postoperative complications (Comprehensive Complication Index, CCI
®
) occurred less frequently (
P
= 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters.
Conclusion:
Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen.
Due to the characteristics of the insidious onset, difficult early diagnosis and high malignancy of pancrea-tic cancer, only a minority of patients still have the chance of surgical resection at the ...time of diagnosis. In recent years, chemotherapy-based preoperative neoadjuvant therapy has been increasingly applied to pancreatic cancer without distant metastases to help achieve tumor downstaging, increase R0 resection rate and improve patient survival. A large number of clinical trials have proven the advantages of neoadjuvant therapy for pancreatic cancer, but there are still many issues to be gradually addressed by further research to reach a consensus.
This study describes late bowel morbidity prospectively assessed in the multi-institutional EMBRACE study on MRI-guided adaptive brachytherapy in locally advanced cervical cancer (LACC).
A total of ...1176 patients were analyzed. Physician reported morbidity (CTCAE v.3.0) and patient reported outcome (PRO) (EORTC QLQ C30/CX24) were assessed at baseline and at regular follow-up.
At 3/5 years the actuarial incidence of bowel morbidity grade 3–4 was 5.0%/5.9%, including incidence of stenosis/stricture/fistula of 2.0%/2.6%. Grade 1–2 morbidity was pronounced with prevalence rates of 28–33% during follow-up. Diarrhea and flatulence were most frequently reported, significantly increased after 3 months and remained elevated during follow-up. Incontinence gradually worsened with time. PRO revealed high prevalence rates. Diarrhea ≥“a little” increased from 26% to 37% at baseline to 3 months and remained elevated, difficulty in controlling bowel increased from 11% to 26% at baseline to 3 months gradually worsening with time. Constipation and abdominal cramps improved after treatment.
Bowel morbidity reported in this large cohort of LACC patients was limited regarding severe/life-threatening events. Mild-moderate diarrhea, flatulence and incontinence were prevalent after treatment with PROs indicating a considerable and clinically relevant burden. Critical knowledge based on the extent and manifestation pattern of treatment-related morbidity will serve future patient management.
Cancer of the anal region Valvo, Francesca; Ciurlia, Elisa; Avuzzi, Barbara ...
Critical reviews in oncology/hematology,
March 2019, 2019-Mar, 2019-03-00, 20190301, Letnik:
135
Journal Article
Recenzirano
Anal canal accounts for 2% of all cancer and its incidence increases with age with a predominance in woman. About 80% of all primary anal canal cancers are squamous; adenocarcinoma arising from the ...glands or glandular ducts shows a behaviour that is similar to that of the adenocarcinoma of the rectum.
Risk factors includes sexually transmitted infection with Human Papillomavirus, cigarette smoking, immunosuppression, and sexual practices. The standard treatment for anal canal is chemo – radiation with a combination of fluoropyrimidines and mitomycin or cisplatin. Salvage surgery may be necessary for residual disease after radiotherapy or chemoradiation, for locoregional relapse and/or for sequelae. In the metastatic setting a multidisciplinary approach is preferred and includes medical treatment, surgery, and RT, if appropriate. Discussing these possible options in the initial stage is of most importance to ensure the best quality of life (QoL) for patients.
There is evidence that regular exercise training has the potential to improve psychological well-being among cancer survivors. However, limited findings are available for individuals with high-grade ...glioma (HGG; WHO grade III and IV) after neurosurgery and undergoing radiochemotherapy. Given this, endurance and strengths training were employed to investigate their impact on symptoms of depression, feelings of stress and anxiety, fatigue, insomnia, and physical fitness, compared to an active control condition.
A total of 29 patients (M = 52.07, SD = 12.45, 55.2% women) participated in this randomized controlled trial (RCT). After neurosurgical treatment and during adjuvant radiotherapy and chemotherapy or combined radiochemotherapy, patients were randomly assigned to the following conditions: Endurance training (n = 10); strengths training (n = 11); active control condition (n = 8). At baseline, three weeks and six weeks later at the end of the study physical fitness was objectively measured with a 6-min walk test (6MWT) and a handgrip test. Participants completed a series of questionnaires covering sociodemographic information, symptoms of depression, stress, anxiety, fatigue, and insomnia. Further, experts rated participants’ severity of symptoms of depression.
Over time and compared to the strengths and active control condition, self-rated symptoms of depression, state and trait anxiety, stress and insomnia decreased in the endurance condition. Over time and compared to the endurance and active control condition, no changes on symptoms of depression, anxiety, stress, or insomnia were observed in the strengths condition. Over time and compared to the endurance and strengths condition, symptoms of depression (self-ratings), stress, insomnia and fatigue decreased in the active control condition. Fatigue increased in both exercising conditions. Over time and irrespective from the study condition, physical fitness did neither improve nor decrease.
The pattern of results suggests that endurance training and an active control condition improved dimensions of depression, stress, and anxiety, while mere strengths training appeared to neither improve, nor decrease dimensions of psychological functioning. Further, exercise interventions did not change physical fitness, but increased fatigue. Overall, endurance training and an active control condition appeared to favorably impact on psychological well-being among patients with high-grade glioma after neurosurgery and undergoing radiochemotherapy.
Radiotherapy is an important regime for treating malignant tumors. There is interest in the development of radiosensitizers to increase the local treatment efficacy under a relatively low and safe ...radiation dose. In this study, we designed Au@Se-R/A nanocomposites (Au@Se-R/A NCs) as nano-radiosensitizer to realize synergistic radiochemotherapy based on the radiotherapy sensitization property of Au nanorods (NRs) and antitumor activity of Se NPs. In vitro studies show that the combined treatment of A375 melanoma cells in culture with NCs and X-ray induces cell apoptosis through alteration in expression of p53 and DNA-damaging genes and triggers intracellular ROS overproduction, leading to greatly enhanced anticancer efficacy. Further studies using clinically used radiotherapy equipment demonstrate that the combined treatment of NCs and X-ray significantly inhibits the tumor growth in vivo and shows negligible acute toxicity to the major organs. Taken together, this study provides a strategy for clinical translation application of nanomedicne in cancer radiochemotherapy.
Prediction of tumor volume using the Cavalieri method may be helpful in management of therapy and evaluation of treatment results. The aim of this study was to adapt the Cavalieri stereological ...method to magnetic resonance imaging for determining volume of nasopharyngeal cancers and assess changes after treatment using the Cavalieri method. Serial MRI images in the sagittal plane were obtained from a total of 33 patients with nasopharyngeal carcinomas (11 with stage T2, 11 with stage T3, and 11 with stage T4 lesions). The images were analyzed retrospectively before and two months following the cessation of radiochemotherapy for comparison. Average tumor volumes before and after treatment in patients with stage T2 were 21. 5±10.5 cm3 and 2.82±3.43 cm
3
, respectively (p=0.000). The respective figures were 35.1±19.0 cm3 and 6.27±7.82 cm
3
(p=0.000) for stage T3 cases, and 62.8±27.8 cm3 and 11. 6±11.9 cm3 (p=0.000) for stage T4. Post-treatment tumor volumes were statistically reduced when compared to pre-treatment volumes in all stages.
