Basic and clinical significance of IGF-I-induced signatures in cancer

The insulin-like growth factor (IGF) system mediates growth, differentiation and developmental processes; it is also involved in various metabolic activities. Deregulation of IGF system expression and action is linked to diverse pathologies, ranging from growth deficits to cancer development. Targeting of the IGF axis emerged in recent years as a promising therapeutic approach in cancer and other medical conditions. Rational use of IGF-I-induced gene signatures may help to identify patients who might benefit from IGF axis-directed therapeutic modalities. In the accompanying research article in BMC Medicine, Rajski et al. show that IGF-I-induced gene expression in primary breast and lung fibroblasts accurately predict outcomes in breast and lung cancer patients

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

Background: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. / Methods: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. / Results: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3–11.3), 5.4 (4.8–5.8) and 2.9 (2.8–4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1–22.4) and 8.3 (7.1–10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). / Conclusions: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies

Novel dual-function CellDetect® staining technology: wedding morphology and tinctorial discrimination to detect cervical neoplasia

<p>Abstract</p> <p>Background</p> <p>A persistent goal of oncologic histochemistry is to microscopically identify neoplasia tinctorially. Consequently, the newly developed CellDetect^®staining technology, that appears to exhibit this property, warrants clinical evaluation. The objective of this study was to compare the diagnostic results using CellDetect^®to the outcomes of standard microscopic examination based on hematoxylin and eosin (H&E) staining for the recognition of different squamous epithelial phenotypes of the uterine cervix.</p> <p>Methods</p> <p>Pairs of adjacent sections were made from 60 cervical biopsy cases that were diagnosed originally as either normal or neoplastic (CIN, SCC). One section of the pair was stained for H&E; the second section, with CellDetect^®. Based on the examination of these pairs by two experienced pathologists, we investigated the following issues:(1) diagnostic agreement between the pathologists on each pair; (2) agreement between H&E and CellDetect^®for each pair (3) tinctorial characteristics in micro-regions (n = 130) evaluated as either normal, reactive or neoplastic.</p> <p>Results</p> <p>Qualitatively, CellDetect^®-stained preparations displayed cyto-morphological detail comparable to H&E images. Tinctorially, <it>non-neoplastic </it>cells appeared green/blue when stained withCellDetect^®, contrasting with cytologically <it>neoplastic </it>foci, where cells of every grade were red/magenta in color. Due to these tinctorial characteristics, even small foci of neoplasia could be readily distinguished that were inconspicuous on H&E at low magnification. In some instances, this prompted re-examination of the H&E and revision of the diagnosis. Quantitatively, we found that despite diagnostic variation between pathologists, in about 3% of the cases, each pathologist made the same diagnosis regardless of whether CellDetect^®or H&E was used, i.e. there was 100% self-agreement for each pathologist between stains. Particularly noteworthy was the finding of a 0% false negative rate, coupled with a 10-15% false positive rate. Regarding specificity, the performance in <it>reactive </it>squamous processes was similar to that observed for morphologically normal squamous epithelium.</p> <p>Conclusions</p> <p>In this first order assessment of clinical applicability, CellDetect^®staining technology was at least comparable to results using H&E, and perhaps surperior. CellDetect^®provided a uniquely useful tinctorial clue for the detection of neoplasia, which exhibited an impressive 0% false negative rate. A more extensive, blinded study is needed to confirm these promising findings.</p

Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer

European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts’ consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer

Variability in chemotherapy delivery for elderly women with advanced stage ovarian cancer and its impact on survival

Given the survival benefits of adjuvant chemotherapy for advanced ovarian cancer (OC), we examined the associations of survival with the time interval from debulking surgery to initiation of chemotherapy and with the duration of chemotherapy. Among patients ⩾65 years with stages III/IV OC diagnosed between 1991 and 2002 in the Surveillance, Epidemiology, and End Results-Medicare database, we developed regression models of predictors of the time interval from surgery to initiation of chemotherapy and of the total duration of chemotherapy. Survival was examined with Cox proportional hazards models. Among 2558 patients, 1712 (67%) initiated chemotherapy within 6 weeks of debulking surgery, while 846 (33%) began treatment >6 weeks. Older age, black race, being unmarried, and increased comorbidities were associated with delayed initiation of chemotherapy. Delay of chemotherapy was associated with an increase in mortality (hazard ratio (HR)=1.11; 95% CI, 1.0–1.2). Among 1932 patients in the duration of treatment analysis, the 1218 (63%) treated for 3–7 months had better survival than the 714 (37%) treated for ⩽3 months (HR=0.84; 95% CI, 0.75–0.94). This analysis represents one of the few studies describing treatment delivery and outcome in women with advanced OC. Delayed initiation and early discontinuation of chemotherapy were common and associated with increased mortality

ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease

The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO–ESGO consensus conference on ovarian cancer was held on April 12–14, 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO–ESGO consensus conference, together with a summary of evidence supporting each recommendation