Detection of recurrences using serum miR-371a-3p during active surveillance in men with stage I testicular germ cell tumours.

BACKGROUND: MiR-371a-3p predicts the presence of a macroscopic non-teratomatous germ cell tumour (GCT). We hypothesised that miR-371a-3p can also detect recurrence during active surveillance (AS) of stage I GCT. METHODS: We prospectively collected serum samples of 33 men. Relative expression of serum miR-371a-3p levels was determined at each follow-up visit using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Recurrence was detected using standard follow-up investigations in 10/33 patients (30%) after a median of 7 months. Directly after orchiectomy, miR-371a-3p levels were not elevated in any of the 15 patients with available post-orchiectomy samples. However, all ten recurring patients exhibited increasing miR-371a-3p levels during follow-up, while miR-371a-3p levels remained non-elevated in all but one patient without recurrence. MiR-371a-3p detected recurrences at a median of 2 months (range 0-5) earlier than standard follow-up investigations. CONCLUSIONS: MiR-371a-3p levels immediately post orchiectomy are not predictive for recurrences and unfortunately cannot support decision-making for AS vs. adjuvant treatment. However, miR-371a-3p detects recurrences reliably and earlier than standard follow-up investigations. If this can be confirmed in larger cohorts, monitoring miR-371a-3p could replace surveillance imaging in seminomatous GCT and reduce the amount of imaging in non-seminomatous GCT. Earlier detection of disease recurrence may also reduce the overall treatment burden.

Prostate cancer patient-derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens.

Patient-derived organoids (PDOs) represent promising preclinical models in various tumor types. In the context of prostate cancer (PCa), however, their establishment has been hampered by poor success rates, which impedes their broad use for translational research applications. Along with the necessity to improve culture conditions, there is a need to identify factors influencing outcomes and to determine how to assess success versus failure in organoid generation. In the present study, we report our unbiased efforts to generate PDOs from a cohort of 81 PCa specimens with diverse pathological and clinical features. We comprehensively analyzed histological features of each enrolled sample (Gleason score, tumor content, proliferation index) and correlated them with organoid growth patterns. We identified improved culture conditions favoring the generation of PCa organoids, yet no specific intrinsic tumor feature was broadly associated with sustained organoid growth. In addition, we performed phenotypic and molecular characterization of tumor-organoid pairs using immunohistochemistry, immunofluorescence, fluorescence in situ hybridization, and targeted sequencing. Morphological and immunohistochemical profiles of whole organoids altogether provided a fast readout to identify the most promising ones. Notably, primary samples were associated with an initial take-rate of 83% (n = 60/72) in culture, with maintenance of cancer cells displaying common PCa alterations, such as PTEN loss and ERG overexpression. These cancer organoids were, however, progressively overgrown by organoids with a benign-like phenotype. Finally, out of nine metastasis samples, we generated a novel organoid model derived from a hormone-naïve lung metastasis, which displays alterations in the PI3K/Akt and Wnt/ß-catenin pathways and responds to androgen deprivation. Taken together, our comprehensive study explores determinants of outcome and highlights the opportunities and challenges associated with the establishment of stable tumor organoid lines derived from PCa patients. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Associations With Definitive Outcomes and Clinical Benefit of Cancer Drugs at the Time of Marketing Approval and in the Postmarketing Period.

BACKGROUND: Most anticancer drugs are approved by regulatory agencies based on surrogate measures. This article explores the variables associated with overall survival (OS), quality of life (QoL), and substantial clinical benefit among anticancer drugs at the time of approval and in the postmarketing period. METHODS: Anticancer drugs approved by the FDA between January 2006 and December 2015 and with postmarketing follow-up until April 2019 were identified. We evaluated trial-level data supporting approval and any updated OS and/or QoL data. We applied the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the ASCO Value Framework (ASCO-VF) to initial and follow-up studies. RESULTS: We found that 58 drugs were approved for 96 indications based on 96 trials. At registration, approval was based on improved OS in 39 trials (41%) and improved QoL in 16 of 45 indications (36%). Postmarketing data showed an improvement in OS for 28 of 59 trials (47%) and in QoL for 22 of 48 indications (46%). At the time of approval, 25 of 94 (27%) and 26 of 80 scorable trials (33%) met substantial benefit thresholds using the ESMO-MCBS and ASCO-VF, respectively. In the postmarketing period, 37 of 69 (54%) and 35 of 65 (54%) trials met the substantial benefit thresholds. Drugs with companion diagnostics and immune checkpoint inhibitors were associated significantly with substantial clinical benefit. CONCLUSIONS: Compared with the time of approval, more anticancer drugs showed improved OS and QoL and met the ESMO-MCBS or ASCO-VF thresholds for substantial benefit over the course of postmarketing time. However, only approximately half of the trials met the threshold for substantial benefit. Companion diagnostic drugs and immunotherapy seemed to be associated with greater clinical benefit.

COVID-19 on Chest Radiographs: A Multireader Evaluation of an Artificial Intelligence System.

Background Chest radiography may play an important role in triage for coronavirus disease 2019 (COVID-19), particularly in low-resource settings. Purpose To evaluate the performance of an artificial intelligence (AI) system for detection of COVID-19 pneumonia on chest radiographs. Materials and Methods An AI system (CAD4COVID-XRay) was trained on 24 678 chest radiographs, including 1540 used only for validation while training. The test set consisted of a set of continuously acquired chest radiographs (n = 454) obtained in patients suspected of having COVID-19 pneumonia between March 4 and April 6, 2020, at one center (223 patients with positive reverse transcription polymerase chain reaction [RT-PCR] results, 231 with negative RT-PCR results). Radiographs were independently analyzed by six readers and by the AI system. Diagnostic performance was analyzed with the receiver operating characteristic curve. Results For the test set, the mean age of patients was 67 years ± 14.4 (standard deviation) (56% male). With RT-PCR test results as the reference standard, the AI system correctly classified chest radiographs as COVID-19 pneumonia with an area under the receiver operating characteristic curve of 0.81. The system significantly outperformed each reader (P < .001 using the McNemar test) at their highest possible sensitivities. At their lowest sensitivities, only one reader significantly outperformed the AI system (P = .04). Conclusion The performance of an artificial intelligence system in the detection of coronavirus disease 2019 on chest radiographs was comparable with that of six independent readers. © RSNA, 2020.

Cognitive behavioral therapy for misophonia: A randomized clinical trial.

BACKGROUND: Patients with misophonia suffer from anger or disgust confronted with specific sounds such as smacking or breathing. Avoidance of cue-related situations results in social isolation and significant functional impairment. This is the first randomized, controlled cognitive behavioral therapy (CBT) trial for misophonia, evaluating the short- and long-term efficacy. METHODS: The evaluator-blinded, randomized clinical trial was conducted from May 2017 until December 2018 at an academic outpatient clinic. Misophonia patients were randomly assigned to 3 months of weekly group-CBT or a waiting list and tested at baseline, 3 months (following CBT or waiting list), 6 months (after cross-over), and 15/18 months (1-year follow-up). CBT consisted of task concentration and arousal reduction, positive affect labeling, and stimulus manipulation. Co-primary outcomes were symptom severity assessed by the Amsterdam Misophonia Scale-Revised (AMISOS-R) and improvement on the Clinical Global Impression-Improvement (CGI-I). Secondary outcomes were self-assessed ratings of general psychopathology (Symptom Checklist-90-Revised [SCL-90-R]) and quality of life (five-dimensional EuroQol [EQ5-D], Sheehan Disability Scale [SDS], WHO Quality of Life-BREF [WHOQoL-BREF]). RESULTS: In all, 54 out of 71 patients were included (mean age, 33.06 [SD, 14.13] years; 38 women [70.4%]) and 46 (85%) completed the study. In the randomized phase, CBT resulted in statistically significant less misophonia symptoms in the short-term (-9.7 AMISOS-R; 95% CI, -12.0 to -7.4; p < .001, d = 1.97). The CBT group had an observed clinical improvement (CGI-I < 3) in 37% compared to 0% in the waiting list group (p < .001). The effect of CBT was maintained at 1-year follow-up on primary and secondary outcomes. CONCLUSIONS: This first randomized control trial shows both short-term and long-term efficacy of CBT for misophonia.

The brassinosteroid receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling.

The brassinosteroid receptor brassinosteroid insensitive 1 (BRI1) is a member of the leucine-rich repeat receptor-like kinase family. The intracellular kinase domain of BRI1 is an active kinase and also encapsulates a guanylate cyclase catalytic centre. Using liquid chromatography tandem mass spectrometry, we confirmed that the recombinant cytoplasmic domain of BRI1 generates pmol amounts of cGMP per µg protein with a preference for magnesium over manganese as a co-factor. Importantly, a functional BRI1 kinase is essential for optimal cGMP generation. Therefore, the guanylate cyclase activity of BRI1 is modulated by the kinase while cGMP, the product of the guanylate cyclase, in turn inhibits BRI1 kinase activity. Furthermore, we show using Arabidopsis root cell cultures that cGMP rapidly potentiates phosphorylation of the downstream substrate brassinosteroid signaling kinase 1 (BSK1). Taken together, our results suggest that cGMP acts as a modulator that enhances downstream signaling while dampening signal generation from the receptor.

Reporting of Randomized Trials in Common Cancers in the Lay Media.

BACKGROUND: Limited data exist about the role of the lay media in the dissemination of results of randomized controlled trials (RCTs) in common cancers. METHODS: Completed phase III RCTs evaluating new drugs in common cancers between January 2005 and October 2016 were identified from ClinicalTrials.gov. Lay media reporting was identified by searching LexisNexis Academic. Scientific reporting was defined as presentation at an academic conference or publication in full. Associations between reporting in the lay media before scientific reporting and study design and sponsorship were evaluated using logistic regression. RESULTS: Of 180 RCTs identified, 52% were reported in the lay media and in 27%, lay media reporting occurred before scientific reporting with an increasing trend over time (p = 0.009). Reporting in the lay media before scientific reporting was associated with positive results (OR: 2.10, p = 0.04), targeted therapy compared to chemotherapy (OR: 4.75, p = 0.006), immunotherapy compared to chemotherapy (OR: 7.60, p = 0.02), and prostate cancer compared to breast cancer (OR: 3.25, p = 0.02). CONCLUSIONS: Over a quarter of all RCTs in common cancers are reported in the lay media before they are reported scientifically with an increasing proportion over time. Positive trials, studies in prostate cancer, and trials of immunotherapy are associated with early reporting in the lay media.

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.

Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease.

BACKGROUND: Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy. RESULTS: After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy. CONCLUSIONS: Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.

Is the neutrophil-to-lymphocyte ratio prognostic of survival outcomes in gynecologic cancers? A systematic review and meta-analysis.

BACKGROUND: Presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in several malignancies. Here, we quantify the effect of NLR on survival in patients with gynecologic cancers, and examine the effect of clinico-pathologic factors on its prognostic value. METHODS: A systematic search of electronic databases was conducted to identify publications exploring the association of pre-treatment blood NLR with overall survival (OS) and event-free survival (EFS) among patients with ovarian, endometrial and cervical cancers. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a p-value (P) were weighted by generic inverse-variance and pooled in a random effects meta-analysis. Subgroup analyses were conducted according to primary tumor type. Meta-regression was performed to evaluate the influence of clinico-pathologic factors on the HR for OS and EFS. All statistical tests were two-sided. RESULTS: Twenty-six studies comprising 10,530 patients were included. Studies used different cut-offs to classify high NLR (range 0.89 to 5.03). The median cut-off for high NLR was 2.95 among twenty-six studies reporting a HR for OS, and 2.79 in seventeen studies reporting EFS outcomes. NLR greater than the cut-off was associated with worse OS (HR 1.65, 95% CI=1.44 to 1.89; P<0.001) and EFS (HR 1.57, 95% CI=1.35 to 1.82; P<0.001). This association was present in all tumor types. Most studies were comprised of patients with both early-stage and advanced disease. In cervical cancer, significant associations between NLR and OS were observed in studies of early- and mixed-stage patients and regression analysis showed a greater magnitude of effect in patients with locally advanced disease and in those who received both chemotherapy and radiation. CONCLUSIONS: High NLR is associated with an adverse OS and EFS in patients with gynecologic malignancies.

Prognostic role of telomere length in malignancies: A meta-analysis and meta-regression.

Telomere length (TL) has been associated with several health conditions including cancer. To quantify the effect of TL on outcomes in malignancies and explore the role of type of TL measurement we conducted a librarian-led systematic search of electronic databases identified publications exploring the prognostic role of TL on cancer outcomes. Overall survival (OS) was the primary outcome measure while other time-to-event endpoints were secondary outcomes. Data from studies reporting a hazard ratio (HR) with 95% confidence interval (CI) and/or p-value were pooled in a meta-analysis. HRs were weighted by generic inverse variance and computed by random effects modeling. All statistical tests were two-sided. Sixty-one studies comprising a total of 14,720 patients were included of which 41 (67%) reported OS outcomes. Overall, the pooled HR for OS was 0.88 (95%CI=0.69-1.11, p=0.28). Long (versus short) telomeres were associated with improved outcomes in chronic lymphatic leukemia (CLL) and urothelial cancer (HR=0.45, 95%CI=0.29-0.71 and HR=0.68, 95%CI=0.46-1.00, respectively), conversely worse OS was seen with hepatocellular carcinoma (HR=1.90, 95%CI=1.51-2.38). Pooled HRs (95% CI) for progression-free survival, relapse/disease-free survival, cancer-specific survival, and treatment-free survival were 0.56 (0.41-0.76), 0.76 (0.53-1.10), 0.72 (0.48-1.10), and 0.48 (0.39-0.60), respectively. There was substantial heterogeneity of tissues and methods used for TL measurement and no clear association between TL and outcome was identified in subgroups. In conclusion, there is inconsistent effect of TL on cancer outcomes possibly due to variable methods of measurement. Standardization of measurement and reporting of TL is warranted before the prognostic value of TL can be accurately assessed.

Under-reporting of harm in clinical trials.

Appropriate safety evaluations of anticancer drugs are crucial to assess their benefit-risk ratio. Substantial evidence shows that clinicians under-report harm in clinical trials, and at least three factors contribute to this problem: assessment of harm by clinicians might not represent the experience of patients; harm might be detected within trials, but is not reported appropriately by investigators or reporting is influenced by sponsors; and short-term follow-up might not detect long-term and potentially serious toxicities. Additionally, because of the selection of patients with good functional status in clinical trials, study results might not apply to patients treated in everyday clinical practice. New approaches for the conduct, oversight, and reporting of clinical trials should include patient-reported assessment of side-effects. Effective pharmacovigilance programmes and large-scale observational studies are needed to improve understanding of the tolerability of anticancer drugs in a real world setting.

Relevance of randomised controlled trials in oncology.

Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing.

Study of testosterone-guided androgen deprivation therapy in management of prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists is an effective initial therapy for men with advanced prostate cancer. LHRH agonists are usually administered indefinitely at a fixed interval. METHODS: We recruited men with advanced prostate cancer who had been on fixed-schedule injections of an LHRH agonist for ≥1 year and had castrate serum testosterone [<1.75 nmol/l (approx. 50 ng/ml)]. Testosterone levels were measured at 6-week intervals and ADT was withheld until testosterone levels were no longer in the castrate range and then reinstituted. Time to reinstitution of ADT was the primary outcome and was analyzed by the Kaplan-Meier method; Cox regression was used to identify factors predicting delay in reinstitution of treatment. Influence on quality-of-life (QoL) was evaluated by the Expanded Prostate Index Composite (EPIC). RESULTS: Forty-six evaluable men who had received LHRH agonist injections every 12 weeks were recruited. Median time to testosterone recovery (defined as testosterone outside the defined castrate level) after previous injection was >1 year. In univariable analysis, lower baseline testosterone [≤1 vs. >1 nmol/l (approx. 30 ng/dl)] and longer time on ADT (>5 vs. ≤5 years) predicted for prolonged time to testosterone recovery, but only lower baseline testosterone remained significant in multivariable analysis (Hazard Ratio = 5.2, P = 0.03). Overall EPIC scores remained stable but improvement from baseline was observed in the hormonal domain (P = 0.002). Median per-patient saving in cost was approximately USD 3,100 (1,050-6,200). CONCLUSIONS: Testosterone-guided ADT reduces exposure to LHRH agonists, with reduction in cost and improvement in some symptoms from ADT. Testosterone-guided ADT should be considered an alternative to fixed schedule treatment by physicians and policy makers.

A foundation for reliable spatial proteomics data analysis.

Quantitative mass-spectrometry-based spatial proteomics involves elaborate, expensive, and time-consuming experimental procedures, and considerable effort is invested in the generation of such data. Multiple research groups have described a variety of approaches for establishing high-quality proteome-wide datasets. However, data analysis is as critical as data production for reliable and insightful biological interpretation, and no consistent and robust solutions have been offered to the community so far. Here, we introduce the requirements for rigorous spatial proteomics data analysis, as well as the statistical machine learning methodologies needed to address them, including supervised and semi-supervised machine learning, clustering, and novelty detection. We present freely available software solutions that implement innovative state-of-the-art analysis pipelines and illustrate the use of these tools through several case studies involving multiple organisms, experimental designs, mass spectrometry platforms, and quantitation techniques. We also propose sound analysis strategies for identifying dynamic changes in subcellular localization by comparing and contrasting data describing different biological conditions. We conclude by discussing future needs and developments in spatial proteomics data analysis.

Identification of trans-golgi network proteins in Arabidopsis thaliana root tissue.

Knowledge of protein subcellular localization assists in the elucidation of protein function and understanding of different biological mechanisms that occur at discrete subcellular niches. Organelle-centric proteomics enables localization of thousands of proteins simultaneously. Although such techniques have successfully allowed organelle protein catalogues to be achieved, they rely on the purification or significant enrichment of the organelle of interest, which is not achievable for many organelles. Incomplete separation of organelles leads to false discoveries, with erroneous assignments. Proteomics methods that measure the distribution patterns of specific organelle markers along density gradients are able to assign proteins of unknown localization based on comigration with known organelle markers, without the need for organelle purification. These methods are greatly enhanced when coupled to sophisticated computational tools. Here we apply and compare multiple approaches to establish a high-confidence data set of Arabidopsis root tissue trans-Golgi network (TGN) proteins. The method employed involves immunoisolations of the TGN, coupled to probability-based organelle proteomics techniques. Specifically, the technique known as LOPIT (localization of organelle protein by isotope tagging), couples density centrifugation with quantitative mass-spectometry-based proteomics using isobaric labeling and targeted methods with semisupervised machine learning methods. We demonstrate that while the immunoisolation method gives rise to a significant data set, the approach is unable to distinguish cargo proteins and persistent contaminants from full-time residents of the TGN. The LOPIT approach, however, returns information about many subcellular niches simultaneously and the steady-state location of proteins. Importantly, therefore, it is able to dissect proteins present in more than one organelle and cargo proteins en route to other cellular destinations from proteins whose steady-state location favors the TGN. Using this approach, we present a robust list of Arabidopsis TGN proteins.

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone.

BACKGROUND: Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). METHODS: We (R.L.A and N.A) retrospectively evaluated outcome in 12 men who were re-treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre. RESULTS: All men were heavily pre-treated for mCRPC with a median of four prior lines of therapy, one of which was AA (given either pre- or post-chemotherapy). Eleven out of 12 (92%) men stopped their first treatment course of AA due to progression and one stopped for financial reasons. Seven men had a PSA decrease ≥50% following their first AA treatment, of which three (46%) had a PSA decrease ≥50% to AA re-treatment. The responses to AA re-treatment were generally short-lived with a median biochemical progression-free survival of 2.3 months and median treatment duration of 3.2 months. No PSA responses to AA re-treatment were seen in five men who did not have an initial PSA response to AA. CONCLUSIONS: Our data suggest that AA re-challenge may have limited benefit in select men with mCRPC, and warrants further formal research.

Simple prognostic score for metastatic castration-resistant prostate cancer with incorporation of neutrophil-to-lymphocyte ratio.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a marker of inflammation, has been reported to be a poor prognostic indicator in prostate cancer. Here we explore the use of the NLR to establish a simple prognostic score for men with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel. METHODS: In the training cohort, the NLR and other known prognostic variables were evaluated among a cohort of chemotherapy-naïve patients treated with thrice-weekly docetaxel at the Princess Margaret Cancer Centre. Significant prognostic variables identified by univariable Cox regression were evaluated by the area under the receiver operating characteristic curves. Multivariable Cox regression was then used to derive a prognostic score where 1 risk point was assigned for each significant variable. The model was externally validated in a cohort of patients treated at the Royal Marsden. RESULTS: Three hundred fifty-seven patients were analyzed in the training cohort. Median age was 71 years, 12% had liver metastasis, and median overall survival (OS) was 14.7 months. Liver metastases, hemoglobin <12 g/dL, alkaline phosphatase >2.0× upper limit of normal (ULN), lactate dehydrogenase >1.2× ULN, and NLR >3 were associated with significantly worse OS in multivariable analysis. Four risk categories were subsequently established with 0, 1, 2, and 3-5 points. Two-year OS rates for these categories were 43%, 37%, 12%, and 3%, respectively. Area under the curve for the training cohort was 0.78 (95% CI, 0.72-0.84) compared with 0.66 (95% CI, 0.58-0.74) for the 215 patients in the validation cohort. CONCLUSIONS: This simple risk score provides good prognostic and discriminatory accuracy for men with mCRPC.

Effect of multifocality and multicentricity on outcome in early stage breast cancer: a systematic review and meta-analysis.

Women with multifocal or multicentric breast tumors (multifocality henceforth) have been reported to have greater probability of nodal metastasis and relapse and worse survival than women with unifocal tumors. However, these associations have been inconsistent and multifocality is not taken into account by staging guidelines and prognostic models. A systematic review of electronic databases identified publications exploring the association between multifocality and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and loco-regional relapse (LRR). The hazard ratios (HRs) for OS and DFS for multifocal compared to unifocal tumors were extracted from multivariable analyses and included in a meta-analysis. For studies not reporting multivariable analyses, odds ratios (OR) were estimated from Kaplan-Meier curves for all endpoints at 5 and 10 years. Twenty-two studies comprising 67,557 women were included. Multifocality was reported in 9.5 % of patients. Classical prognostic factors were well balanced between unifocal and multifocal populations. In multivariable analyses, multifocality was associated with significantly worse OS (HR 1.65; P = 0.02), and a non-significant association with worse DFS (HR 1.96; P = 0.07). In univariable analyses, multifocality was associated with worse OS, DFS, DSS, and LRR at 5 years (OR 1.39, P = 0.02; OR 1.52, P = 0.02; OR 1.56, P = 0.03; and OR 3.23, P = 0.02, respectively). Similar estimates were observed at 10 years, but statistical significance was only reached for DSS and LRR. Mutifocality appears to be associated with a worse prognosis, however, substantial inter-study heterogeneity limits the precise determination of increased risk. Further validation of the independent prognostic impact of multifocality is warranted.

Factors impacting survival following second surgery in patients with glioblastoma in the temozolomide treatment era, incorporating neutrophil/lymphocyte ratio and time to first progression.

Patients with progressive glioblastoma (GBM) have a poor prognosis. Neutrophil/lymphocyte ratio (NLR), a host inflammatory marker, is prognostic in several solid tumors. The prognostic impact of either NLR, or time from first surgery for GBM to first progression (TTP), in patients undergoing second surgery, has not been assessed. Patients undergoing second surgery for GBM were retrospectively reviewed. Primary outcome was overall survival (OS) and Cox proportional hazard models were used to assess the prognostic value of baseline characteristics including TTP and NLR. Univariable and multivariable analysis (MVA) of OS from second surgery were performed using accelerated failure time Weibull model. Of 584 patients with GBM, 107 (18 %) underwent second surgery between 01/04 and 12/11. Patients who underwent second surgery had longer OS versus those having primary surgery alone; 20.9 versus 9.9 months (P < 0.001). Median OS from second surgery in patients with NLR ≤ 4 versus NLR > 4 was 9.7 versus 5.9 months (log rank P = 0.02). The NLR retained its prognostic significance for survival on MVA (time ratio [TR] 1.65, 95 % confidence interval [CI] 1.15-2.35, P < 0.01). No chemotherapy post second surgery (TR 0.23, 95 % CI 0.16-0.33, P < 0.001) portended worse survival. In patients undergoing second surgery, when TTP was ≤ 12 months, 12-24 months, or >24 months, median OS from second surgery was 7.2, 7.0 and 6.3 months, respectively (P = 0.6). A NLR > 4 prior to second surgery is a poor prognostic factor in GBM and later progression is associated with longer survival in patients but not in longer survival after second surgery.