Correlation between hematological parameters and PET/CT metabolic parameters in patients with head and neck cancer.

BACKGROUND Systemic inflammation is predictive of the overall survival in cancer patients and is related to the density of immune cells in the tumor microenvironment of cancer, which in turn correlates with 18F -fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) metabolic parameters (MPs). The density of tumor-infiltrating lymphocytes (TILs) in the microenvironment has the potential to be a biomarker that can be used clinically to optimize patient selection in oropharyngeal head and neck squamous cell carcinoma (HNSCC). There is little to no data regarding the association of systemic inflammation with PET/CT-MPs, especially in HNSCC. This study aimed to evaluate the correlation between markers of host inflammation, namely blood neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), with the PET/CT-MPs standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor, derived from FDG-PET/CT in patients with nonmetastatic (cM0) HNSCC before treatment. We hypothesized that NLR and PLR at baseline are positively correlated with PET/CT-MPs. METHODS A retrospective review of consecutive patients with HNSCC with a pretreatment PET/CT was performed. NLR and PLR were computed using complete blood counts measured within 10 days before the start of any treatment. The correlation between NLR and PLR with PET/CT-MPs was evaluated with Spearman's rho test. RESULTS Seventy-one patients were analyzed. Overall survival (OS) at 1, 2, and 3 years was 86%, 76%, and 68%. PLR was found to be correlated with MTV (rho = 0.26, P = .03) and TLG (rho = 0.28, P = .02) but not with maximum SUV or mean SUV. There was no correlation between NLR and the analyzed PET/CT-MPs. TLG was associated with worse survival in uni- and multivariable analysis, but no other PET/CT-MPs were associated with either OS or disease-specific survival (DSS). NLR and PLR were associated with OS and DSS on uni- and multivariable analysis. CONCLUSIONS In patients with HNSCC before any treatment such as definitive radio (chemo)therapy or oncologic surgery followed by adjuvant RT, baseline PLR correlated with MTV and TLG but not with SUV. NLR was not correlated with any PET/CT-MPs analyzed in our study. Confirmatory studies are needed, and a potential interaction between tumor microenvironment, host inflammation, and FDG-PET/CT measures warrants further investigation

Treatment Outcomes for Men with Clinical Stage II Nonseminomatous Germ Cell Tumours Treated with Primary Retroperitoneal Lymph Node Dissection: A Systematic Review

CONTEXT Guidelines recommend primary retroperitoneal lymph node dissection (RPLND) as a treatment option for tumour marker-negative stage II nonseminomatous germ cell tumour (NSGCT). OBJECTIVE To review the literature on oncological outcomes for men with stage II NSGCT treated with RPLND. EVIDENCE ACQUISITION A systematic review of studies describing clinicopathological outcomes following primary RPLND in stage II NSGCT was conducted in the MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews databases according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement. Baseline data, perioperative and postoperative parameters, and oncological outcomes were collected. EVIDENCE SYNTHESIS In total, 12 of 4387 studies were included, from which we collected data for 835 men. Among men with clinical stage II NSGCT, pathological stage II was confirmed in 615 of 790 patients (78%). Most studies administered adjuvant chemotherapy in cases with large lymph nodes, multiple affected lymph nodes, or persistently elevated tumour markers. Recurrence was observed in 12-40% of patients without adjuvant chemotherapy and 0-4% of patients who received adjuvant chemotherapy. CONCLUSIONS The literature describing RPLND in clinical stage II NSGCT is heterogeneous and no meta-analysis was possible, but RPLND can provide accurate staging and may be curative in selected patients. PATIENT SUMMARY We reviewed the literature to summarise results after surgical removal of enlarged lymph nodes in the back of the abdomen in men with testis cancer. This procedure provides accurate information on how far the cancer has spread and may provide a cure in selected patients

Impact of differing methodologies for serum miRNA-371a-3p assessment in stage I testicular germ cell cancer recurrence.

INTRODUCTION Current evidence shows that serum miR-371a-3p can identify disease recurrence in testicular germ cell tumour (TGCT) patients and correlates with tumour load. Despite convincing evidence showing the advantages of including miR-371a-3p testing to complement and overcome the classical serum tumour markers limitations, the successful introduction of a serum miRNA based test into clinical practice has been impeded by a lack of consensus regarding optimal methodologies and lack of a universal protocol and thresholds. Herein, we investigate two quantitative real-time PCR (qRT-PCR) based pipelines in detecting disease recurrence in stage I TGCT patients under active surveillance, and compare the sensitivity and specificity for each method. METHODS Sequential serum samples collected from 33 stage I TGCT patients undergoing active surveillance were analysed for miR-371a-3p via qRT-PCR with and without an amplification step included. RESULTS Using a pre-amplified protocol, all known recurrences were detected via elevated miR-371a-3p expression, while without pre-amplification, we failed to detect recurrence in 3/10 known recurrence patients. For pre-amplified analysis, sensitivity and specificity was 90% and 94.4% respectively. Without amplification, sensitivity dropped to 60%, but exhibited 100% specificity. DISCUSSION We conclude that incorporating pre-amplification increases sensitivity of miR-371a-3p detection, but produces more false positive results. The ideal protocol for quantification of miR-371a-3p still needs to be determined. TGCT patients undergoing active surveillance may benefit from serum miR-371a-3p quantification with earlier detection of recurrences compared to current standard methods. However, larger cross-institutional studies where samples are processed and data is analysed in a standardised manner are required prior to its routine clinical implementation

Impact of differing methodologies for serum miRNA-371a-3p assessment in stage I testicular germ cell cancer recurrence

INTRODUCTION Current evidence shows that serum miR-371a-3p can identify disease recurrence in testicular germ cell tumour (TGCT) patients and correlates with tumour load. Despite convincing evidence showing the advantages of including miR-371a-3p testing to complement and overcome the classical serum tumour markers limitations, the successful introduction of a serum miRNA based test into clinical practice has been impeded by a lack of consensus regarding optimal methodologies and lack of a universal protocol and thresholds. Herein, we investigate two quantitative real-time PCR (qRT-PCR) based pipelines in detecting disease recurrence in stage I TGCT patients under active surveillance, and compare the sensitivity and specificity for each method. METHODS Sequential serum samples collected from 33 stage I TGCT patients undergoing active surveillance were analysed for miR-371a-3p via qRT-PCR with and without an amplification step included. RESULTS Using a pre-amplified protocol, all known recurrences were detected via elevated miR-371a-3p expression, while without pre-amplification, we failed to detect recurrence in 3/10 known recurrence patients. For pre-amplified analysis, sensitivity and specificity was 90% and 94.4% respectively. Without amplification, sensitivity dropped to 60%, but exhibited 100% specificity. DISCUSSION We conclude that incorporating pre-amplification increases sensitivity of miR-371a-3p detection, but produces more false positive results. The ideal protocol for quantification of miR-371a-3p still needs to be determined. TGCT patients undergoing active surveillance may benefit from serum miR-371a-3p quantification with earlier detection of recurrences compared to current standard methods. However, larger cross-institutional studies where samples are processed and data is analysed in a standardised manner are required prior to its routine clinical implementation

Circulating DNA and survival in solid tumors

[Background]: The ability to undertake molecular analysis to inform on prognosis and predictors of response to therapy is limited by accessibility of tissue. Measurement of total circulating free DNA (cfDNA) or circulating tumor DNA (ctDNA) in peripheral blood may allow easier access to tumor material and help to predict clinical outcomes. [Methods]: A systematic review of electronic databases identified publications exploring the association between cfDNA or ctDNA and overall survival (OS) in solid tumors. HRs for OS were extracted from multivariable analyses and included in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance and random-effect modeling. For studies not reporting multivariable analyses, univariable ORs were estimated from Kaplan-Meier curves for OS at 1 and 3 years. [Results]: Thirty-nine studies comprising 4,052 patients were included in the analysis. Detection of ctDNA was associated with a significantly worse OS in multivariable analyses [HR, 2.70; 95% confidence interval (CI), 2.02-3.61; P < 0.001). Similar results were observed in the univariable analyses at 3 and 1 year (OR, 4.83; 95% CI, 3.20-7.28; P < 0.001).There was also a statistically significant association between high total cfDNA and worse OS for studies reporting multivariable and univariate data at 3 years (HR, 1.91; 95% CI, 1.59-2.29; P < 0.001 and OR, 2.82; 95% CI, 1.93-4.13; P < 0.001, respectively). [Conclusions]: High levels of total cfDNA and presence of ctDNA are associated with worse survival in solid tumors. [Impact]: Circulating DNA is associated with worse outcome in solid tumors.This work was supported by grants from CRIS cancer foundation (to A. Ocaña and A. Pandiella).Peer Reviewe

Role of cooperative groups and funding source in clinical trials supporting guidelines for systemic therapy of breast cancer

Clinical research is conducted by academia, cooperative groups (CGs) or pharmaceutical industry. Here, we evaluate the role of CGs and funding sources in the development of guidelines for breast cancer therapies. We identified 94 studies. CGs were involved in 28 (30%) studies while industry either partially or fully sponsored 64 (68%) studies. The number of industry funded studies increased over time (from 0% in 1976 to 100% in 2014; p for trend = 0.048). Only 10 (11%) government or academic studies were identified. Studies conducted by GCs included a greater number of subjects (median 448 vs. 284; p = 0.015), were more common in the neo/adjuvant setting (p < 0.0001), and were more often randomized (p = 0.018) phase III (p < 0.0001) trials. Phase III trial remained significant predictor for CG-sponsored trials (OR 7.1 p = 0.004) in a multivariable analysis. Industry funding was associated with higher likelihood of positive outcomes favoring the sponsored experimental arm (p = 0.013) but this relationship was not seen for CG-sponsored trials (p = 0.53). ASCO, ESMO, and NCCN guidelines were searched to identify systemic anti-cancer therapies for early-stage and metastatic breast cancer. Trial characteristics and outcomes were collected. We identified sponsors and/or the funding source(s) and determined whether CGs, industry, or government or academic institutions were involved. Chi-square tests were used for comparison between studies. Industry funding is present in the majority of studies providing the basis for which recommendations about treatment of breast cancer are made. Industry funding, but not CG-based funding, was associated with higher likelihood of positive outcomes in clinical studies supporting guidelines for systemic therapy

Cell-Free DNA Genomic Profiling and Its Clinical Implementation in Advanced Prostate Cancer.

Most men with prostate cancer (PCa), despite potentially curable localized disease at initial diagnosis, progress to metastatic disease. Despite numerous treatment options, choosing the optimal treatment for individual patients remains challenging. Biomarkers guiding treatment sequences in an advanced setting are lacking. To estimate the diagnostic potential of liquid biopsies in guiding personalized treatment of PCa, we evaluated the utility of a custom-targeted next-generation sequencing (NGS) panel based on the AmpliSeq HD Technology. Ultra-deep sequencing on plasma circulating free DNA (cfDNA) samples of 40 metastatic castration-resistant PCa (mCRPC) and 28 metastatic hormone-naive PCa (mCSPC) was performed. CfDNA somatic mutations were detected in 48/68 (71%) patients. Of those 68 patients, 42 had matched tumor and cfDNA samples. In 21/42 (50%) patients, mutations from the primary tumor tissue were detected in the plasma cfDNA. In 7/42 (17%) patients, mutations found in the primary tumor were not detected in the cfDNA. Mutations from primary tumors were detected in all tested mCRPC patients (17/17), but only in 4/11 with mCSPC. AR amplifications were detected in 12/39 (31%) mCRPC patients. These results indicate that our targeted NGS approach has high sensitivity and specificity for detecting clinically relevant mutations in PCa

Metastatic Potential of Small Testicular Germ Cell Tumors: Implications for Surveillance of Small Testicular Masses.

Incidental detection of urogenital tumors has increased in recent decades owing to the greater use of ultrasonography and cross-sectional imaging. For patients with low-risk prostate cancer or small renal masses, active surveillance represents a valid treatment option. Similarly, for men with small testicular masses <10 mm, active surveillance has been discussed as an alternative to surgery, although little is known regarding the behavior of small testicular germ cell tumors (GCTs). In the Swiss Austrian German Testicular Cancer Cohort Study we identified 849 patients (546 seminoma, 303 nonseminoma) treated with radical inguinal orchiectomy for GCT with a median tumor diameter of 35 mm. A tumor diameter <10 mm was observed in 25 patients (13 seminoma, 12 nonseminoma). Of these, five patients (20%) presented with primary metastatic disease, all of whom had elevated tumor markers and nonseminomatous GCTs. Two patients (8%) with initially localized disease (1 seminoma, 1 nonseminoma) and without elevated tumor markers experienced relapse at 4 mo (nonseminoma) and 14 mo (seminoma) after orchiectomy, despite the fact that the latter had received adjuvant chemotherapy. These findings highlight the metastatic potential of small testicular GCTs and raise the question of whether active surveillance for small testicular masses is safe. Patient summary This study on testicular cancer assesses the metastatic potential of small testicular germ cell tumors. Men with small testicular masses should be counseled about the malignant potential of small testicular germ cell tumors

Neutrophils in cancer: prognostic role and therapeutic strategies

Expression of high levels of immune cells including neutrophils has been associated with detrimental outcome in several solid tumors and new strategies to decrease their presence and activity are currently under clinical development. Here, we review some of the relevant literature of the role of neutrophils in different stages of the oncogenic process including tumor initiation, growth, proliferation or metastatic spreading and also focus on how neutrophil counts or the neutrophil-to-lymphocyte ratio may be used as a prognostic and predictive biomarker. Strategies to avoid the deleterious effects of neutrophils in cancer and to reduce their activity are discussed. Examples for such strategies include inhibition of CXCR1 and CXCR2 to decrease migration of neutrophils to tumoral areas or the inhibition of granulocyte colony stimulating factor to decrease the amount of neutrophils which has shown efficacy in preclinical models.Instituto de Salud Carlos III (PI16/01121), ACEPAIN; Diputación de Albacete and CRIS Cancer Foundation (to AO). BAE (Beca Ampliación de Estudios) to AO for his stay at Yale University, CT, USA. Ministry of Economy and Competitiveness of Spain (BFU2015–71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to AP). The work carried out in our laboratories receive support from the European Community through the regional development funding program (FEDER).Peer Reviewe

Much has changed in the last decade except overall survival: A Swiss single center analysis of treatment and survival in patients with stage IV non-small cell lung cancer.

BACKGROUND:Molecular therapies for cancers with targetable driver mutations and immunotherapies have revolutionized treatment of non-small cell lung cancer (NSCLC) during the last decade. International treatment guidelines began integrating targeted therapies in 2009 and immunotherapies in 2015. The aim of this study was to examine whether the benefits described for these new therapies in pivotal phase III trials have been translated to a real world patient population. PATIENTS AND METHODS:Data from all consecutive patients diagnosed with stage IV NSCLC diagnosed at a community hospital in Switzerland between 2007 and 2018 were analyzed. Three groups of patients were compared, namely patients diagnosed before 2009 (group 1), between 2009 and 2015 (introduction of targeted therapies, group 2) and after 2015 (introduction of immunotherapies, group 3). The primary outcome was overall survival (OS). Time to treatment failure was a secondary outcome. Both endpoints were estimated using the Kaplan Meyer method and compared by log-rank test. RESULTS:408 patients were included. Patient characteristics were similar in the three groups. Median OS in groups 1, 2, and 3 was 9.8 (95% CI, 6.2 to 13.4), 9.9 (95% CI, 7.6 to 12.1) and 8.6 (95% CI, 6.6 to 10.5) months, respectively (p = 0.5). Across groups patients treated with targeted- and immunotherapies had a significantly better outcome than those treated with chemotherapy or best supportive care (p<0.001). Nevertheless, OS remained unchanged between groups despite adequate molecular testing and integration of targeted- and immunotherapies. Over time, the patient population got more morbid with respect to tumor burden (p = 0.02) and co-morbidities (p = 0.02). CONCLUSIONS:While selected subgroups of patients may benefit from new therapies, outcome in this unselected population of patients with stage IV NSCLC treated in daily practice has not improved over the last decade