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Biochimica Et Biophysica Acta. Reviews... Aug 2020Chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) are able to alter the composition of the tumor immune microenvironment (TIME). Understanding the effect...
BACKGROUND
Chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) are able to alter the composition of the tumor immune microenvironment (TIME). Understanding the effect of these modalities on the TIME could aid in the development of improved treatment strategies. Our aim was to systematically review studies investigating the influence of CT, RT or CRT on different TIME markers.
METHODS
The EMBASE (Ovid) and PubMed databases were searched until January 2019 for prospective or retrospective studies investigating the dynamics of the local TIME in cancer patients (pts) treated with CT, RT or CRT, with or without targeted agents. Studies could either compare baseline and follow-up specimens - before and after treatment - or a treated versus an untreated cohort. Studies were included if they used immunohistochemistry and/or flow cytometry to assess the TIME.
RESULTS
In total we included 110 studies (n = 8850 pts), of which n = 89 (n = 6295 pts) compared pre-treatment to post-treatment specimens and n = 25 (n = 2555 pts) a treated versus an untreated cohort (4 studies conducted both comparisons). For several tumor types (among others; breast, cervical, esophageal, ovarian, rectal, lung mesothelioma and pancreatic cancer) remodeling of the TIME was observed, leading to a potentially more immunologically active microenvironment, including one or more of the following: an increase in CD3 or CD8 lymphocytes, a decrease in FOXP3 Tregs and increased PD-L1 expression. Both CT and CRT were able to immunologically alter the TIME.
CONCLUSION
The TIME of several tumor types is significantly altered after conventional therapy creating opportunities for concurrent or sequential immunotherapy.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Chemoradiotherapy, Adjuvant; Clinical Trials as Topic; Flow Cytometry; Humans; Immunohistochemistry; Immunotherapy; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasms; Treatment Outcome; Tumor Microenvironment
PubMed: 32540465
DOI: 10.1016/j.bbcan.2020.188386 -
Cancers Apr 2019The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an... (Review)
Review
The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90-1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA) tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26-1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.
PubMed: 31035512
DOI: 10.3390/cancers11050588 -
Frontiers in Neurology 2019Cancer patients who have undergone radiotherapy may have an increased risk of subsequent stroke. A clear and detailed understanding of this risk has not been...
Cancer patients who have undergone radiotherapy may have an increased risk of subsequent stroke. A clear and detailed understanding of this risk has not been established. A search for research articles published from January 1990 to November 2017 in the English language was conducted. Subsequent stroke risk in cancer survivors was compared using relative risk (RR) and 95% confidence intervals (CI) according to whether or not radiotherapy was given. A total of 12 eligible studies were identified including 57,881 total patients. All studies were retrospective, as no prospective studies were identified. The meta-analysis revealed a higher overall risk of subsequent stroke in cancer survivors/patients given radiotherapy compared to those not given radiotherapy (RR: 2.09, 95% CI: 1.45, 3.16). In addition, compared to patients not given radiotherapy, there was an increased risk of subsequent stroke for radiotherapy treated patients with Hodgkin's lymphoma (RR: 2.81, 95% CI: 0.69, 4.93) or head/neck/brain/nasopharyngeal cancer (RR: 2.16, 95% CI: 1.16, 3.16), for patients younger than 40 years (RR: 3.53, 95% CI: 2.51, 4.97) or aged 40-49 years (RR: 1.23, 95% CI: 1.09, 1.45) and for patients treated in Asia (RR: 1.88, 95% CI: 1.48, 2.29), the United States (RR: 1.62, 95% CI: 1.01, 2.23), or in Europe (RR: 4.11, 95% CI 2.62, 6.45). The available literature indicates an approximate overall doubling of the subsequent stroke risk in cancer patients given radiotherapy. The elevated risk was generally statistically significant according to cancer type, baseline patient age and region or country where treatment was given. Caution is required in interpreting these findings due to the heterogeneity of populations represented and lack of standardization and completeness across published studies. Further, if real, we cannot conclude the extent to which patient, treatment and/or investigational factors are responsible for this apparent elevated risk. An objective and more detailed understanding of the risks of radiotherapy, and how to prevent them, is urgently required. It is the responsibility of all who provide cancer services to ensure that the experience of all their patients is documented and analyzed using quality registries.
PubMed: 30930843
DOI: 10.3389/fneur.2019.00233 -
Dose-response : a Publication of... 2019Radiation therapy induces acute and chronic radiological toxicity, in particular hematological toxicity (HT). This study aimed to explore the mechanistic clue and... (Review)
Review
Analysis of mRNA Expression Patterns in Peripheral Blood Cells of 3 Patients With Cancer After the First Fraction of 2 Gy Irradiation: An Integrated Case Report and Systematic Review.
BACKGROUND
Radiation therapy induces acute and chronic radiological toxicity, in particular hematological toxicity (HT). This study aimed to explore the mechanistic clue and potential predictors at the messenger RNA (mRNA) level.
MATERIALS AND METHODS
Peripheral blood was collected from 3 patients with cervical cancer (CC), nasopharynx cancer (NC), and tongue cancer (TC) after the first 2 Gy fraction of radiotherapy (RT). High-throughput sequencing was used to assess mRNA profiles.
RESULTS
Eleven genes, such as ALAS2(5-aminolevulinate synthase), SLC4A1(solute carrier family 4 member 1), (hemoglobin subunit gamma 2), (TNF α-induced protein 3), (period circadian clock 1), (coiled-coil domain containing 136), (chromosome 9 open reading frame 84), (interleukin 1β), (FosB protooncogene), (nuclear receptor subfamily 4), (polymerase family member 15), had overlapping expression changes in all 3 cancers of which 3 (, and ) are suggested as potential predictors for the early diagnosis of HT after RT.
CONCLUSIONS
may be useful predictors of HT in patients after RT. Eleven overlapping expression mRNAs among 3 cancers might be potential predictors for early diagnosis of radiation toxicity in patients.
PubMed: 30833875
DOI: 10.1177/1559325819833474 -
Scientific Reports Sep 2018Targeted therapy is lagging behind in esophageal adenocarcinoma (EAC). To guide the development of new treatment strategies, we provide an overview of the prognostic... (Meta-Analysis)
Meta-Analysis
Targeted therapy is lagging behind in esophageal adenocarcinoma (EAC). To guide the development of new treatment strategies, we provide an overview of the prognostic biomarkers in resectable EAC treated with curative intent. The Medline, Cochrane and EMBASE databases were systematically searched, focusing on overall survival (OS). The quality of the studies was assessed using a scoring system ranging from 0-7 points based on modified REMARK criteria. To evaluate all identified prognostic biomarkers, the hallmarks of cancer were adapted to fit all biomarkers based on their biological function in EAC, resulting in the features angiogenesis, cell adhesion and extra-cellular matrix remodeling, cell cycle, immune, invasion and metastasis, proliferation, and self-renewal. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were derived by random effects meta-analyses performed on each hallmarks of cancer feature. Of the 3298 unique articles identified, 84 were included, with a mean quality of 5.9 points (range 3.5-7). The hallmarks of cancer feature 'immune' was most significantly associated with worse OS (HR 1.88, (95%CI 1.20-2.93)). Of the 82 unique prognostic biomarkers identified, meta-analyses showed prominent biomarkers, including COX-2, PAK-1, p14ARF, PD-L1, MET, LC3B, IGFBP7 and LGR5, associated to each hallmark of cancer.
Topics: Adenocarcinoma; Biomarkers, Tumor; Esophageal Neoplasms; Humans; Prognosis; Proportional Hazards Models; Survival Analysis
PubMed: 30185893
DOI: 10.1038/s41598-018-31548-6 -
Annals of Surgical Oncology Sep 2018Duodenal adenocarcinoma (DA) is a rare tumor for which survival data per treatment modality and disease stage are unclear. This systematic review and meta-analysis aims... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Duodenal adenocarcinoma (DA) is a rare tumor for which survival data per treatment modality and disease stage are unclear. This systematic review and meta-analysis aims to summarize the current literature on patient outcome after surgical, (neo)adjuvant, and palliative treatment in patients with DA.
METHODS
A systematic search was performed according to the preferred reporting items for systematic reviews and meta-analyses guidelines, to 25 April 2017. Primary outcome was overall survival (OS), specified for treatment strategy or disease stage. Random-effects models were used for the calculation of pooled odds ratios per treatment modality. Included papers were also screened for prognostic factors.
RESULTS
A total of 26 observational studies, comprising 6438 patients with DA, were included. Of these, resection with curative intent was performed in 71% (range 53-100%) of patients, and 29% received palliative treatment (range 0-61%). The pooled 5-year OS rate was 46% after curative resection, compared with 1% in palliative-treated patients (OR 0.04, 95% confidence interval [CI] 0.02-0.09, p < 0.0001). Both segmental resection and pancreaticoduodenectomy allowed adequate assessment of lymph node involvement and resulted in similar OS. Lymph node involvement correlated with worse OS (pooled 5-year survival rate 21% for nodal metastases vs. 65% for node-negative disease; OR 0.17, 95% CI 0.11-0.27, p < 0.0001). In the current literature, no survival benefit for adjuvant therapy after curative resection was found.
CONCLUSION
Resection with curative intent, either pancreaticoduodenectomy or segmental resection, and lack of nodal metastases, favors survival for DA. Further studies exploring multimodality (neo)adjuvant therapy are warranted to investigate their benefit.
Topics: Adenocarcinoma; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Duodenal Neoplasms; Humans; Lymphatic Metastasis; Metastasectomy; Neoadjuvant Therapy; Palliative Care; Pancreaticoduodenectomy; Survival Rate; Treatment Outcome
PubMed: 29946997
DOI: 10.1245/s10434-018-6567-6 -
International Journal of Hyperthermia :... Nov 2018In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this...
OBJECTIVE
In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients.
METHODS AND MATERIALS
We searched MEDLINE and Embase, supplemented by handsearching, for clinical studies involving hyperthermia in pancreatic cancer patients. The quality of studies was evaluated using the Oxford Centre for Evidence-Based Medicine levels of evidence. Primary outcome was treatment efficacy; we calculated overall response rate and the weighted estimate of the population median overall survival (m) and compared these between hyperthermia and control cohorts.
RESULTS
Overall, 14 studies were included, with 395 patients with locally advanced and/or metastatic pancreatic cancer of whom 248 received hyperthermia. Patients were treated with regional (n = 189), intraoperative (n = 39) or whole-body hyperthermia (n = 20), combined with chemotherapy, radiotherapy or both. Quality of the studies was low, with level of evidence 3 (five studies) and 4. The six studies including a control group showed a longer m in the hyperthermia groups than in the control groups (11.7 vs. 5.6 months). Overall response rate, reported in three studies with a control group, was also better for the hyperthermia groups (43.9% vs. 35.3%).
CONCLUSIONS
Hyperthermia, when added to chemotherapy and/or radiotherapy, may positively affect treatment outcome for patients with pancreatic cancer. However, the quality of the reviewed studies was limited and future randomised controlled trials are needed to establish efficacy.
Topics: Aged; Female; Humans; Hyperthermia, Induced; Male; Middle Aged; Pancreatic Neoplasms; Prognosis
PubMed: 29168401
DOI: 10.1080/02656736.2017.1401126 -
Oncotarget Sep 2017Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA... (Review)
Review
BACKGROUND
Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect.
MATERIALS AND METHODS
Here, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported.
RESULTS
Sixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didn't find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data.
CONCLUSION
PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.
PubMed: 28978184
DOI: 10.18632/oncotarget.19079 -
Andrology Sep 2017The impact of phosphodiesterase type 5 inhibitor (PDE5I) treatment modality (on-demand vs. daily), PDE5I half-life and time from surgery to PDE5I prescription on the... (Meta-Analysis)
Meta-Analysis Review
Erectile function recovery in men treated with phosphodiesterase type 5 inhibitor administration after bilateral nerve-sparing radical prostatectomy: a systematic review of placebo-controlled randomized trials with trial sequential analysis.
The impact of phosphodiesterase type 5 inhibitor (PDE5I) treatment modality (on-demand vs. daily), PDE5I half-life and time from surgery to PDE5I prescription on the achievement of drug-assisted erectile function (EF) recovery is uncertain. We systematically reviewed published randomized clinical trials (RCTs). We performed meta-analyses of data on 2317 men treated with PDE5Is after nerve-sparing radical prostatectomy (NSRP). A PubMed and SCOPUS search was performed for trials published from 1 January 1969 to 30 June 2016. PDE5Is are effective in achieving drug-assisted recovery of erectile function (EF). From a statistical standpoint, these studies were subjected to Trial Sequential Analysis to determine whether the pooled data were adequately powered to verify the study outcomes. On-demand treatment with PDE5Is was significantly better than daily treatment in recovering drug-assisted EF. This effect was maintained even when the drugs were stratified according with half-life. Although not based on head-to-head trials, Avanafil used on-demand was the most effective PDE5I in recovering drug-assisted EF. Whereas tadalafil was equally effective when used both on-demand and daily, vardenafil significantly improved drug-assisted EF recovery only when used on-demand. The start of PDE5I treatment six months or more after surgery compared to treatment started earlier did not negatively affect the rate of drug-assisted EF recovery or the possibility to have successful intercourse based on the Sexual Encounter Profile question-3 (SEP-3). Current trials do not support the hypothesis that PDE5I use recovers drug-unassisted EF, although chronic low-dose tadalafil administration may help to preserve erectile tissue integrity. Potential shortcomings in the trials design may partially explain these disappointing results and several questions concerning the recovery of drug-unassisted EF remain unanswered. Thus, there is a need for well-designed new RCTs requiring changes in the timing of PDE5I administration as well as in the dose and the treatment duration.
Topics: Erectile Dysfunction; Humans; Male; Penile Erection; Phosphodiesterase 5 Inhibitors; Prostatectomy; Randomized Controlled Trials as Topic
PubMed: 28787547
DOI: 10.1111/andr.12403 -
Scientific Reports Jun 2017Trastuzumab combined with chemotherapy is standard of care for HER2 positive advanced gastro-esophageal cancers. The reported prevalence of HER2 discordance between... (Meta-Analysis)
Meta-Analysis
Trastuzumab combined with chemotherapy is standard of care for HER2 positive advanced gastro-esophageal cancers. The reported prevalence of HER2 discordance between primary tumors and corresponding metastases varies, hampering uniform patient selection for HER2 targeted therapy. This meta-analysis explores the influence of HER2 assessment methods on this discordance and investigates the prevalence of HER2 discordance in gastro-esophageal adenocarcinomas. PubMed, Embase and Cochrane databases were searched until January 2016. Differences in discordance rate between strict and broad(er) definitions of HER2 status were assessed using random-effect pair-wise meta-analysis. Random-effect single-arm meta-analyses were performed to assess HER2 discordance and the prevalence of positive and negative conversion. A significantly lower discordance rate in HER2 status between primary tumors and corresponding metastases was observed using a strict vs. broad definition of HER2 status (RR = 0.58, 95%CI 0.41-0.82), with a pooled discordance rate of 6.2% and 12.2%, respectively. Using the strict definition of HER2 assessment pooled overall discordance was 7% (95%CI 5-10%). The lowest discordance rates between primary tumors and corresponding metastasis are observed when using a strict method of HER2 positivity. Treatment outcomes of different studies will be better comparable if selection of eligible patients for HER2 targeted therapy is based on this strict definition.
Topics: Adenocarcinoma; Antineoplastic Agents; Esophageal Neoplasms; Gene Amplification; Humans; Neoplasm Metastasis; Receptor, ErbB-2; Stomach Neoplasms; Trastuzumab; Treatment Outcome
PubMed: 28600510
DOI: 10.1038/s41598-017-03304-9