Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (n = 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval [CI]: 40.9–95.2, p = 0.019; and NR vs. 56.1 months, 95% CI: 40.9–95.2, p = 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease, BRCA1/2 status and stage (HR 2.48, 95% CI: 1.03–5.99, p = 0.043, and HR 2.91, 95% CI: 1.11–7.64, p = 0.03, respectively). In the IDS group (n = 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).

Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8–17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6–9.2), and median OS (mOS) of 20.6 months (95% CI 13.6–28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2–22.2] and 10.3 [IQR 7.4–14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5–8.6) versus 7.5 months (95% CI 6.5–10.1, p = 0.03), and 16.4 (95% CI 9.3–27.5) versus 24.2 months (95% CI 17.2–NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.

This paper introduces local distance-based generalized linear models. These models extend (weighted) distance-based linear models first to the generalized linear model framework. Then, a nonparametric version of these models is proposed by means of local fitting. Distances between individuals are the only predictor information needed to fit these models. Therefore, they are applicable, among others, to mixed (qualitative and quantitative) explanatory variables or when the regressor is of functional type. An implementation is provided by the R package dbstats, which also implements other distance-based prediction methods. Supplementary material for this article is available online, which reproduces all the results of this article.

Background: Selection and persistence of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations during treatment interruptions (TIs) has been attributed to the long plasma half-life of these drugs. However, little is known about the contribution of variable NNRTI plasma levels before a TI. We evaluated the selection of NNRTI-related mutations and the coefficient of variation of NNRTI plasma concentrations during different TI periods. Methods: The selection of NNRTI-related mutations was examined in 50 HIV type-1 (HIV-1)-infected patients on a virologically suppressive regimen who underwent TI guided by CD4 ⁺ T-cell counts and plasma viraemia. Population and clone-based sequencing of the reverse transcriptase coding region was performed using plasma HIV-1 RNA samples during TI and proviral DNA from peripheral blood mononuclear cells before TI. NNRTI plasma concentrations were determined by HPLC. Results: In 7/50 treated patients, de novo and transient NNRTI-related mutations appeared when treatment was interrupted. Emergence of resistant variants (including K103N, Y181C or G190S) after interruption was associated with a higher coefficient of variation in NNRTI plasma concentrations during the treatment period. Moreover, minority HIV-1 variants containing different resistance patterns (V106I/A, K103R/E or Y188C/D/H) were detected regardless of NNRTI concentrations. Conclusions: The emergence of NNRTI-associated mutations during TI appears to be associated with the variation of NNRTI plasma concentrations during the preceding treatment period. The selection of minority HIV-1 variants with different patterns of NNRTI resistance in the absence of drug pressure should be considered for the efficacy of future NNRTI-containing antiretroviral regimens.

Purpose: Medicines in special situations (MSS) refer to off‐label or to unlicensed drugs under investigation (compassionate use). Our objectives were to evaluate characteristics and to estimate overall survival (OS), event‐free survival (EFS), and the duration of treatment (DT) of MSS used for cancer treatment at a multicentre comprehensive cancer institution.Methods: Retrospective cohort study on adult cancer patients for whom an MSS treatment was requested (January 2011–December 2020). A descriptive analysis was performed and median OS and EFS and 95% confidence intervals (CIs) were estimated. Survival curves were stratified by type of tumor, ECOG (Eastern Cooperative Oncology Group) performance status (PS), age, sex, treatment stage and type of drug (mechanism of action and target).Results: Treatment was initiated in 2092 episodes (1930 patients) out of 2377 MSS episodes (2189 patients) requested, 33% for hematological treatment and 87% for advanced stage cancer. Median OS (months) was 21.1 (95% CI 19.4–22.7), median EFS was 5.6 (95% CI 5.1–6.0) months, and median DT was 4.5 [0.0; 115.3] months.OS and EFS statistically significantly favored female patients, ECOG PS ≥2 episodes showed worse OS and EFS outcomes (p < 0.0001). Statistically significant differences in survival were found within solid and hematological cancer, disease stage, drug mechanism of action, and type of cancer (p < 0.001) but not for age. Survival outcomes by tumor subtype and drug are presented both globally and separately based on disease stage.Conclusion: MSS uses are practiced across almost all cancer types, mostly for advanced disease. ECOG PS ≥2, along with advanced disease, was related to worse survival. Information about real‐world outcomes is valuable and contributes to better decision‐making regarding MSS and our experience in this field could be of interest for other colleagues.

Purpose: Molecular subtype classifications in glioblastoma may detect therapy sensitivities. IHC would potentially allow the identification of molecular subtypes in routine clinical practice. Experimental Design: Formalin-fixed, paraffin-embedded tumor samples of 124 uniformly treated, newly diagnosed patients with glioblastoma were submitted to RNA sequencing, IHC, and immune-phenotyping to identify differences in molecular subtypes associated with treatment sensitivities. Results: We detected high molecular and IHC overlapping of the The Cancer Genome Atlas (TCGA) mesenchymal subtype with instrinsic glioma subtypes (IGS) cluster 23 and of the TCGA classical subtype with IGS cluster 18. IHC patterns, gene fusion profiles, and immune-phenotypes varied across subtypes. IHC revealed that the TCGA classical subtype was identified by high expression of EGFR and low expression of PTEN, while the mesenchymal subtype was identified by low expression of SOX2 and high expression of two antibodies, SHC1 and TCIRG1, selected on the basis of RNA differential transcriptomic expression. The proneural subtype was identified by frequent positive IDH1 expression and high Olig2 and Ki67 expression. Immune-phenotyping showed that mesenchymal and IGS 23 tumors exhibited a higher positive effector cell score, a higher negative suppressor cell score, and lower levels of immune checkpoint molecules. The cell-type deconvolution analysis revealed that these tumors are highly enriched in M2 macrophages, resting memory CD4+ T cells, and activated dendritic cells, indicating that they may be ideal candidates for immunotherapy, especially with anti-M2 and/or dendritic cell vaccination. Conclusions: There is a subset of tumors, frequently classified as mesenchymal or IGS cluster 23, that may be identified with IHC and could well be optimal candidates for immunotherapy.