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PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer. [ABSTRACT FROM AUTHOR]

Background: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab. Objective: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment. Methods: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment. Results: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/μL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen. Conclusion: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results. [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant PD-1 blockade combined with chemotherapy is a promising treatment for resectable non-small cell lung cancer (NSCLC), yet the immunological mechanisms contributing to tumor regression and biomarkers corresponding to different pathological responses remain unclear. Methods: Using dynamic and paired blood samples from NSCLC patients receiving neoadjuvant chemoimmunotherapy, we analyzed the frequencies of CD8 + T-cell and Treg subsets and their dynamic changes during neoadjuvant treatment through flow cytometry. Cytokine profiles and function-related gene expression of CD8 + T cells and Tregs were analyzed through flow cytometry and mRNA-seq. Infiltrating T-cell subsets in resected tissues from patients with different pathological responses were analyzed through multiplex immunofluorescence. Results: Forty-two NSCLC patients receiving neoadjuvant chemoimmunotherapy were enrolled and then underwent surgical resection and pathological evaluation. Nineteen patients had pCR (45%), 7 patients had MPR (17%), and 16 patients had non-MPR (38%). In patients with pCR, the frequencies of CD137 + CD8 + T cells (P = 0.0475), PD-1 + Ki-67 + CD8 + T cells (P = 0.0261) and Tregs (P = 0.0317) were significantly different from those of non-pCR patients before treatment. pCR patients usually had low frequencies of CD137 + CD8 + T cells, PD-1 + Ki-67 + CD8 + T cells and Tregs, and their AUCs were higher than that of tissue PD-L1 expression. Neoadjuvant chemoimmunotherapy markedly improved CD8 + T-cell proliferation and activation, especially in pCR patients, as the frequencies of CD137 + CD8 + (P = 0.0136) and Ki-67 + CD8 + (P = 0.0391) T cells were significantly increased. The blood levels of cytokines such as IL-2 (P = 0.0391) and CXCL10 (P = 0.0195) were also significantly increased in the pCR group, which is consistent with the high density of activated cytotoxic T cells at the tumor site (P < 0.0001). Conclusion: Neoadjuvant chemoimmunotherapy drives CD8 + T cells toward a proliferative and active profile. The frequencies of CD137 + CD8 + T cells, PD-1 + Ki-67 + CD8 + T cells and Tregs at baseline might predict the response to neoadjuvant chemoimmunotherapy in NSCLC patients. The increase in IL-2 and CXCL10 might reflect the chemotaxis and enrichment of cytotoxic T cells at the tumor site and a better response to neoadjuvant chemoimmunotherapy. [ABSTRACT FROM AUTHOR]

Blinatumomab is an immunotherapy drug approved for the treatment of acute lymphoblastic leukemia. Since not all patients respond to blinatumomab, markers are needed to predict the efficacy of blinatumomab in individual patients. We hypothesized that the pre-treatment blast-to-lymphocyte ratio would predict blinatumomab efficacy. To examine this possibility, we conducted a post hoc analysis using data from the TOWER Clinical Trials (NCT02013167). Multivariate analysis showed that, along with the treatment groups, each of the following was independently correlated with superior progression-free survival: salvage-treatment phase, allogeneic stem cell transplantation, and pre-treatment ratio of bone marrow blasts-to-peripheral blood lymphocytes < 25. [ABSTRACT FROM AUTHOR]

Introduction: Gestational hypertension (GH) is defined as the presence of systolic blood pressure (BP) ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg, measured at least 4 h apart after 20 weeks of gestation. Early identification of women at high-risk of developing GH could contribute significantly towards improved maternal and fetal outcomes. Objectives: To determine early metabolic biomarkers in women with GH as compared with normotensive women. Methods: Serum samples were collected from subjects during three stages of their pregnancy: 8–12 weeks, 18–20 weeks and after 28 weeks (< 36 weeks) of gestation and studied using nuclear magnetic resonance (NMR) metabolomics approach. Multivariate and univariate analyses were performed to determine the significantly altered metabolites in GH women. Results: A total of 10 metabolites, including isoleucine, glutamine, lysine, proline, histidine, phenylalanine, alanine, carnitine, N-acetyl glycoprotein and lactic acid were observed to be significantly downregulated during all pregnancy stages in women with GH as compared with controls. Furthermore, expression of 5 metabolites in the first trimester i.e., phenylalanine [area under the curve (AUC) = 0.745], histidine [AUC = 0.729], proline [AUC = 0.722], lactic acid [AUC = 0.722], and carnitine [AUC = 0.714] exhibited highest potential in discriminating GH from normotensive women. Conclusion: The present study is the first of its kind to identify significantly altered metabolites that have the potential to discriminate between women at risk of developing GH and normotensive women across three trimesters of pregnancy. This opens up the possibility of exploring these metabolites as potential early predictive markers of GH. [ABSTRACT FROM AUTHOR]

Depressive patients suffer from a complex of symptoms of varying intensity compromising their mood, emotions, self-concept, neurocognition, and somatic function. Due to a mosaic of aetiologies involved in developing depression, such as somatic, neurobiological, (epi-)genetic factors, or adverse life events, patients often experience recurrent depressive episodes. About 20–30% of these patients develop difficult-to-treat depression. Here, we describe the design of the GEParD (Genetics and Epigenetics of Pharmaco- and Psychotherapy in acute and recurrent Depression) cohort and the DaCFail (Depression-associated Cardiac Failure) case–control protocol. Both protocols intended to investigate the incremental utility of multimodal biomarkers including cardiovascular and (epi-)genetic markers, functional brain and heart imaging when evaluating the response to antidepressive therapy using comprehensive psychometry. From 2012 to 2020, 346 depressed patients (mean age 45 years) were recruited to the prospective, observational GEParD cohort protocol. Between 2016 and 2020, the DaCFail case–control protocol was initiated integrating four study subgroups to focus on heart-brain interactions and stress systems in patients > 50 years with depression and heart failure, respectively. For DaCFail, 120 depressed patients (mean age 60 years, group 1 + 2), of which 115 also completed GEParD, and 95 non-depressed controls (mean age 66 years) were recruited. The latter comprised 47 patients with heart failure (group 3) and 48 healthy subjects (group 4) of a population-based control group derived from the Characteristics and Course of Heart Failure Stages A–B and Determinants of Progression (STAAB) cohort study. Our hypothesis-driven, exploratory study design may serve as an exemplary roadmap for a standardized, reproducible investigation of personalized antidepressant therapy in an inpatient setting with focus on heart comorbidities in future multicentre studies. [ABSTRACT FROM AUTHOR]

Background: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer. Methods: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed. Results: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported. Conclusions: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer. Trial registration: Clinical trial registration NCT03816839. [ABSTRACT FROM AUTHOR]

Purpose: The Naples prognostic score (NPS) is a prognostic index based on the nutritional and inflammatory status. However, its utility in predicting postoperative complications (POCs) has not been examined in rectal cancer (RC). We evaluated the predictive value of the preoperative NPS for POCs in RC. Methods: We retrospectively analyzed 235 patients who underwent surgery for RC. The NPS was calculated based on serum albumin, serum total cholesterol, the neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR). Severe POCs were defined as Clavien-Dindo classification grade ≥ III. The optimal cut-off value of the NPS was determined by a receiver operator characteristic (ROC) curve analysis. The NPS, NLR, LMR, platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP)-to-albumin ratio (CAR), Glasgow prognostic score (GPS), Onodera prognostic nutritional index (PNI) and controlling nutritional status score (CONUT) were investigated as inflammation-based and/or nutritional markers. Predictors of severe POCs were analyzed by logistic regression modeling. Results: Severe POCs were observed in 64 patients (27.2%). Male sex, operation time (> 257 min), blood loss (≥ 30 mL), albumin (< 4.0 g/dL), CRP (≥ 1.0 mg/dL), total cholesterol (≤ 180 mg/dL), NPS (≥ 2), LMR (≥ 3.48), PLR (≥ 103.6), CAR (> 0.025), GPS (≥ 1), PNI (< 48.1) and CONUT (≥ 2) were significantly associated with severe POCs. The multivariate analysis revealed that male sex, operation time (> 257 min), and a high NPS (≥ 2) were independent predictors of severe POCs. The ROC curve analysis revealed that the NPS had the greatest predictive value among the inflammation-based and/or nutritional markers. Conclusion: The NPS is a valuable predictor of severe POCs in RC. [ABSTRACT FROM AUTHOR]

Summary: Diagnosis and decision-making in the treatment of breast cancer patients is vastly dependent on the exploration of biomarkers. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are long-standing biomarkers, which determine the breast cancer subtype. In current practice, gene expression analyses further define the molecular breast cancer subtype and give additional information on disease characteristics. Prognostic biomarkers provide information regarding recurrence risk and survival. Predictive biomarkers, such as programmed cell death ligand 1 expression, are tools for identifying patients who can benefit from specific therapy regimens in order to choose the best treatment option for the patient. While some biomarkers are affordable and readily available, others remain technically complex to access. Translational research builds the bridge from discovering novel biomarkers in preclinical studies to testing their application utility in the clinical setting. Integrating translational studies into clinical trials is therefore essential to find novel and reliable biomarkers for an optimal personalized treatment approach for patients with breast cancer. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) has become a common global health problem as prevalence continues to rise. It is often associated with increased risk of colorectal cancer (CRC) development. Limitations in current IBD biomarker-based diagnosis hinder the accuracy of early detection of CRC progression. Therefore, in this study, we proposed the use of transcription factor (TF)-based biomarkers that can potentially detect the transition of IBD to CRC. Various bioinformatic analysis and online database validations, and RT-qPCR validations were performed to identify possible diagnostic TFs. RUNX1 was identified as a promising TF that regulates 106 IBD/CRC-related genes. The incorporation of RUNX1 in combination with currently known IBD biomarkers, FEV + NFKB1 + RELA, achieved a comparable sensitivity and specificity scores of 99% and 87%, respectively, while RUNX1 in combination with known CRC markers, CEA + TIMP1 + CA724 + CA199, achieved a sensitivity and specificity score of 97% and 99%, respectively. Furthermore, a small pilot RT-qPCR-based analysis confirmed a demarcated shift in expression profiles in CA724, CEA, RUNX1 and TIMP1 in IBD patients compared to CRC patients’ tissue samples. Specifically, CA724 is noticeably elevated in IBD, while the levels of CEA, RUNX1 with TIMP1 are probable genes that may be employed in discerning IBD progression to CRC. Therefore, these preliminary results once validated in large patient cohorts could potentially have a significant impact on CRC disease stratification, resulting in a more precise prediction for treatment and treatment outcomes, especially in South African patients. [ABSTRACT FROM AUTHOR]

The study aimed to evaluate mean platelet volume (MPV), platelet distribution width (PDW), and platecrit in children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), to assess the predictive value of these platelet activation markers for adverse outcomes, and to correlate their levels with various data in these patients. This prospective cohort study included 60 children with PAH-CHD as group I and 60 children with CHD and no PAH as group II. Another 60 healthy children of matched age and sex served as the control group. All included children were evaluated by echocardiography. MPV, PDW, and platecrit were also measured using an automated blood counter. All patients were followed up for death or readmission for 6 months. MPV, PDW, and platecrit were significantly higher in group I compared to group II and the control group and they correlated well with increasing severity of PAH. MPV, PDW, and platecrit positively correlated with right ventricular diameter and mean pulmonary artery pressure, however they correlated negatively with right ventricular systolic and diastolic function. The best cut-off of platelet activation markers levels to predict poor prognosis in group I was > 11.2 FL with 75% sensitivity and 96.6% specificity for MPV, > 12.7 FL with 75% sensitivity and 61.5% specificity for PDW, and > 0.505% with 75% sensitivity and 93.2% specificity for platecrit. MPV, PDW, and platecrit were elevated in children with PAH-CHD and found to be good predictive markers for poor prognosis in these children. [ABSTRACT FROM AUTHOR]

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Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Immune thrombocytopenia (ITP) was defined using the International Consensus Guidelines as a platelet count <100×109/L in the absence of other causes or disorders that may be associated with thrombocytopenia. For patients without response to first-line treatment or refractory, TPO receptor agonist (RA) is an ideal choice. This study was to evaluate the efficiency and safety of eltrombopag for multi-line failed Chinese patients with immune thrombocytopenia (ITP) and analyze the possible factors that may contribute to the differences based on personal characteristics. Thirty-five multi-line failed ITP patients who received eltrombopag treatment were enrolled retrospectively at the First Affiliated Hospital of Zhejiang Chinese Medical University from January 2018 to August 2020. The general information, peripheral hemogram changes, count of bone marrow megakaryocyte (MK), peripheral T cell subsets were recorded, the response, and adverse effects, was evaluated. Results showed that the overall, complete, and partial response rates were 54.3% (n=19), 48.6% (n=17), and 5.7% (n=2) respectively to eltrombopag in our center. The overall response rate of patients with decreased MK was 70%, which was unexpectedly higher than that of the patient with increased or normal MK count (52.9% and 40%, respectively). For patients with poorer eltrombopag response group, more NK cells were found in peripheral blood, and the patient with decreased MK have a higher level of T helper (Th) cells and regulatory T (Treg) cells. Nine eltrombopag-related adverse events were reported, and most commonly were upper respiratory tract infection (8.6%), elevated alanine transaminase (ALT, 5.7%), and venous thrombosis (5.7%). In conclusion, this study revealed that ITP patients with decreased megakaryocyte respond well to eltrombopag, and the abnormality of NK cells may play a role in patients with a poor eltrombopag response. [ABSTRACT FROM AUTHOR]

Differences between computer-assisted image analysis (CAI) algorithms may cause discrepancies in the identification of immunohistochemically stained immune biomarkers in biopsies of breast cancer patients. These discrepancies have implications for their association with disease outcome. This study aims to compare three CAI procedures (A, B and C) to measure positive marker areas in post-neoadjuvant chemotherapy biopsies of patients with triple-negative breast cancer (TNBC) and to explore the differences in their performance in determining the potential association with relapse in these patients. A total of 3304 digital images of biopsy tissue obtained from 118 TNBC patients were stained for seven immune markers using immunohistochemistry (CD4, CD8, FOXP3, CD21, CD1a, CD83, HLA-DR) and were analyzed with procedures A, B and C. The three methods measure the positive pixel markers in the total tissue areas. The extent of agreement between paired CAI procedures, a principal component analysis (PCA) and Cox multivariate analysis was assessed. Comparisons of paired procedures showed close agreement for most of the immune markers at low concentration. The probability of differences between the paired procedures B/C and B/A was generally higher than those observed in C/A. The principal component analysis, largely based on data from CD8, CD1a and HLA-DR, identified two groups of patients with a significantly lower probability of relapse than the others. The multivariate regression models showed similarities in the factors associated with relapse for procedures A and C, as opposed to those obtained with procedure B. General agreement among the results of CAI procedures would not guarantee that the same predictive breast cancer markers were consistently identified. These results highlight the importance of developing additional strategies to improve the sensitivity of CAI procedures. [ABSTRACT FROM AUTHOR]

Striatal dopamine is important in paranoid attributions, although its computational role in social inference remains elusive. We employed a simple game-theoretic paradigm and computational model of intentional attributions to investigate the effects of dopamine D2/D3 antagonism on ongoing mental state inference following social outcomes. Haloperidol, compared with the placebo, enhanced the impact of partner behaviour on beliefs about the harmful intent of partners, and increased learning from recent encounters. These alterations caused substantial changes to model covariation and negative correlations between self-interest and harmful intent attributions. Our findings suggest that haloperidol improves belief flexibility about others and simultaneously reduces the self-relevance of social observations. Our results may reflect the role of D2/D3 dopamine in supporting self-relevant mentalising. Our data and model bridge theory between general and social accounts of value representation. We demonstrate initial evidence for the sensitivity of our model and short social paradigm to drug intervention and clinical dimensions, allowing distinctions between mechanisms that operate across traits and states., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples ( N  = 1,384) of medication-free individuals with first-episode and recurrent MDD ( N  = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls ( N  = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals ( N  = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter ( N  = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter ( N  = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) ( β  = -18.3, 95% CI (-34.3 to -2.3), P  = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response., Competing Interests: Competing interestsS.R.A. has consulted for Indoc Research Canada. B.W.D. has received research support from Boehringer-Ingelheim, Compass, Pathways, NIMH, Otsuka, and Uson and honoraria for consulting from Aya Biosciences, Myriad Neuroscience, Otsuka, Sophren Therapeutics, Cerebral Therapeutics, Sage. C.H.Y.F. has received grant funding from Brain and Behavior (NARSAD), Eli Lilly and Co. Milken Institute, Flow Neuroscience, MRC, NIMH, Rosetrees Trust, and Wellcome Trust and is Section Editor of Brain Research Bulletin. C.J.H. serves as a consultant for P1vital, Lundbeck, Servier, and Compass Pathways. She holds grant income from Zogenix and J&J. S.H.K. has received funding for consulting or speaking engagements from Abbvie, Boehringer-Ingelheim, Janssen, Lundbeck, Lundbeck Institute, Merck, Otsuka Pfizer, Sunovion, and Servier. He has received research support from Abbott, Brain Canada, CIHR (Canadian Institutes of Health Research), Janssen, Lundbeck, Ontario Brain Institute, Otsuka, Pfizer, and SPOR (Canada’s Strategy for Patient-Oriented Research). He has stock/stock options in Field Trip Health. G.M.K. has received honoraria as a speaker for Sage Biogen and as a consultant for Sanos. H.S.M. has received grant funding from NIH and consulting and IP licenses fees from Abbott Labs. A.M.M. has received research support from Eli Lilly, Janssen, and The Sackler Trust. A.M.M. has also received speaker fees from Illumina and Janssen. W.E.C. serves on the National Advisory Board of the George West Mental health Foundation, as a board member of Hugarheill ehf (an Icelandic company dedicated to the prevention of depression), and on the scientific advisory boards of AIM for Mental Health and the Anxiety and Depression Association of America; he is supported by the Mary and John Brock Foundation, the Pitts Foundation, and the Fuqua family foundations, and he receives book royalties from John Wiley. H.S. has received grant funding from NIH. S.C.S. received research support from Brain Canada, CIHR (Canadian Institutes of Health Research), Ontario Brain Institute, and CFI (Canadian Foundation for Innovation). S.C.S. is a founder and shareholder of ADMdx, Inc. D.T. has received grant funding from NIH. M.H.T. received research support from NIH, PCORI, and AFSP, is a consultant for Alkermes Inc., Alto Neuroscience Inc, Axsome Therapeutics, Boegringer Ingelheim, GH Research, GreenLight VitalSign6 Inc, Heading Health, Inc., Janssen Pharmaceutical, Legion Health, Merck Sharp & Dohme Corp., Mind Medicine Inc., Navitor, Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka Canada Pharmaceutical Inc, Otsuka Pharmaceutical Development & Commercialization, Inc. (MDD section adviser), SAGE Therapeutics, Signant Health, and Takeda Pharmaceuticals Inc and receives editorial compensation from Oxford University Press. A.H.Y. reports the following conflicts of interest: paid lectures and advisory boards for the following companies: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis; consultant to Johnson & Johnson and to Livanova; received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova; principal investigator in the Restore-Life VNS registry study funded by LivaNova; UK chief investigator for Novartis MDD study MIJ821A12201; principal investigator on ESKETINTRD3004: ‘An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression’; principal investigator on ‘The Effects of Psilocybin on Cognitive Function in Healthy Participants’; principal investigator on ‘The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)’; no shareholdings in pharmaceutical companies; deputy editor of BJPsych Open. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK); Janssen (UK). R.Z. is a private psychiatrist service provider at The London Depression Institute and co-investigator on a Livanova-funded observational study of vagus nerve stimulation for depression. R.Z. has received honoraria for talks at medical symposia sponsored by Lundbeck as well as Janssen. He has collaborated with EMIS PLC and advises Depsee Ltd. He is affiliated with the D’Or Institute of Research and Education, Rio de Janeiro, and advises the Scients Institute, USA. Authors A. Singh, A. Stolicyn, B.R.G., B.N.F., C.C.F., C.-G.Y., C.D., D.A., D.W., G.E., H.C.W., I.H.G., I.M.A., I.S., J.F.W.D., J.Q., J.S., J.A.G., K.H., K.S.C., K.Q., M.P.P., M.A., M.D.S., M.G., Q.G., R.E., S.H., S.R., T.A.V., T.C., T.W., V.G.F., and Y.F. declare that they have no competing interests., (© The Author(s) 2024.)

Purpose: Spindle cell oncocytomas (SCOs) are very rare tumors of the posterior pituitary with potential for locally aggressive behaviour. Their treatment includes surgery and possibly radiotherapy, however other options are lacking. Somatostatin receptors (SSTs) are a possible therapeutic target for somatostatin analogues and their expression has been demonstrated recently in closely related pituicytomas, but there are no data about their presence in SCOs.Methods: We collected five cases of SCO from four patients including one recurrent case. Immunohistochemical detection of TTF1, GFAP, CD68, SST1, SST2, SST3, SST5 and D2 dopamine receptor (D2DR) was performed. Intensity, percentage of positive cells and pattern of expression was evaluated in semiquantitative fashion. Protein expression of SST1−5 and D2DR was further evaluated by western blot.Results: Mean patient age was 61.8 years (range 47-71 years) with male to female ratio 1:1. In one patient, samples from the original tumor and its recurrence 16 years later were assessed. TTF1 was positive in all five cases, no expression of GFAP and CD68 was seen. Immunohistochemical expression of SST1 was noted in 1/5 cases, SST2 in 2/5 cases, including recurrent case but not the original case. SST3 was expressed in 3/5 tumors and D2 dopamine receptor in 4/5 cases. Western blot was successfully performed in four samples. SST2, SST3 and D2DR expression was identified in all the samples, including two cases originally negative for SST2 and one case negative for SST3 by immunohistochemistry. The number of positive cells and level of expression varied among different areas of the same tumors. No expression of SST5 was observed. In the patient with the recurrent tumor, intensity of SST2, SST3 and D2DR expression varied between original tumor and its recurrence.Conclusions: We demonstrated presence of different SST subtypes and D2DR in spindle cell oncocytomas. The most commonly expressed subtype was SST2 and SST3, while no expression of SST5 was observed. Expression showed spatial heterogeneity and temporal changes as seen in the recurrent case. The biological meaning of SSTs expression in SCOs is unclear as well as whether it may be exploited in treatment of selected cases. [ABSTRACT FROM AUTHOR]

Liposomal therapies opened the chapter of nanomedicine, in 1995, with the approval of liposomal doxorubicin (Doxil®) for the treatment of numerous types of cancer. For the first time, liposomes permitted the employment of potent chemotherapeutic agents with improved pharmacokinetic and pharmacodynamic profiles, with less undesired side effects. Liposomal therapies allow the drug encapsulation and more selective delivery in the tumor bed, particularly due to the enhanced permeation and retention effect. These unique characteristics explain why liposomal therapies are being increasingly considered as alternatives in cancer therapy and represent an important research field with the recent approval for clinical use and emergent formulations in clinical trials. Even so, the response rate of liposomal therapies varies between 5 and 71%, and they are still indistinguishably given to every patient. As already well-demonstrated for conventional chemotherapies and targeted therapies, there is also the need for predictive biomarkers that allow a better use of liposomal drugs, with higher patient quality of life. Our aim in this review was to address the approved liposomal therapies and to summarize the information concerning possible predictive markers of response in their various clinical applications, to personalize each patient treatment and maximize its efficacy. [ABSTRACT FROM AUTHOR]

The identification of informative biomarkers that could predict the treatment response is particularly important in the triple-negative (TN) breast cancer, which is characterized by biological diversity. The aim of this study was to investigate the impact of vascular endothelial growth factor receptor (VEGFR2) expression and its gene polymorphisms on pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in Russian patients with TN breast cancer. We performed a retrospective analysis of 70 women with operable TN breast cancer, who underwent NCT with 5-fluorouracil, adriamycin, and cyclophosphamide (FAC) or cyclophosphamide, adriamycin, and capecitabine (CAX) between 2007 and 2013. VEGFR2 expression was evaluated before NCT by immunohistochemistry. TaqMan SNP assays were used for genotyping KDR − 604T>C (rs2071559) and KDR 1192G>A (rs2305948) polymorphisms. The pCR was used as an end-point in the treatment efficacy analysis. In the univariate analysis, the pCR rate was strongly associated with young age (P = 0.004), high Ki67 expression (P = 0.012), lymph node negativity (P = 0.023) as well as with positive VEGFR2 expression (P = 0.019) and the CAX regimen (P = 0.005). In the multivariate analysis, only patient’s age (P = 0.005) and pre-NCT VEGFR2 expression (P = 0.048) remained significant predictors of pCR. The pCR rate was higher in the CAX-treated patients than that in the FAC-treated patients (P = 0.005). Our results revealed that − 604TT genotype of rs2071559 and age < 50 years were correlated with a pCR in the CAX-treated patients. VEGFR2 expression in pre-NCT tumors and KDR gene polymorphism can be considered as additional predictive molecular markers of pCR in Russian TN breast cancer patients treated with NCT. [ABSTRACT FROM AUTHOR]

Background: The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate.Patients and methods: We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression.Results: We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis.Conclusion: The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described. [ABSTRACT FROM AUTHOR]

Many therapies are available for patients with rheumatoid arthritis (RA) while biological therapies have limited effects in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). In both cases, biomarkers predicting drug response would be very useful to guide clinicians in their choice. We performed a systematic review to evaluate the value of lymphocyte phenotyping as a marker of therapeutic response. Of the 1063 articles retrieved, 39 fulfilled inclusion criteria and were included in the present review (25 for RA, 10 for SLE, and 4 for pSS). Lymphocyte phenotyping was described as a biomarker of therapeutic response in many studies, but most results could not be confirmed by independent teams using multivariate analysis. The most consistent result might be the association between rituximab response and the levels of memory B cells before therapy, although some studies were controversial. Thus, lymphocyte phenotyping cannot yet be proposed as a biomarker of response in rheumatic autoimmune diseases. The lack of reproducibility between studies may be explained by technical issues influencing lymphocyte phenotyping so standardization procedures should be developed for future studies. The patients' characteristics vary between studies, and large population studies, including a wide range of patients' characteristics and biomarkers, are required to provide predictive models for clinical outcomes. The use of new flow cytometry techniques such as single-cell mass cytometry technology might also help finder reliable biomarkers in the future. [ABSTRACT FROM AUTHOR]

In this work, we studied molecular-biological factors leading to cervical cancer. The clinicopathologic characteristics and immunohistochemical features of 185 patients with cervical pathologies associated with human papillomavirus infection were examined. Immunohistochemical features analyzed included histone deacetylases (HDAC1, HDAC2) and DNA methyltransferases (DNMT1, DNMT2). Strong correlations of these factors with cervical pathologies including malignancies were identified. [ABSTRACT FROM AUTHOR]

Ductal carcinoma in situ of the breast comprises nearly 25 % of all diagnoses of breast cancer. The current paradigm for management of DCIS consists of breast-conserving surgery followed by post-operative radiotherapy. The goal of the treatment of DCIS is to reduce the risk of local recurrence (and invasive local recurrence) to prevent the detrimental psychological impact of recurrence and minimize the need for additional treatment. A number of clinical, pathological, and molecular variables have been identified as predictive markers of recurrence and can be used to help risk stratify women with this diagnosis. We present here a review of current markers of recurrence, risk prediction tools, and future directions. [ABSTRACT FROM AUTHOR]

Cytogenetic data have established relevance for prognostication in myeloma. Also, certain chromosomal aberrations were associated with an increased risk of progression of smoldering myeloma to active disease. The impact of cytogenetic and molecular data on treatment decisions is however limited. Myeloma patients with a t(4;14) have been shown to benefit from bortezomib treatment, while thalidomide treatment has a detrimental effect in cases with del17p13. The discovery of marked intraclonal heterogeneity has influence on therapeutic concepts to treat plasma cell disease, but so far no relevance for guiding treatment in individual cases. Cereblon is the molecular target of immunomodulatory substances, and expression levels have been linked to treatment outcome under thalidomide, lenalidomide, and pomalidomide treatment. Alternative splicing has been described for cereblon, and relevance of different isoforms for drug sensitivity is currently under study. So far no reliable clinical test exists to predict for response to immunomodulatory substances. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to evaluate the objective clinical response (cOR), pathological complete response (pCR), and progression-free survival (PFS) in 231 Russian patients with four subtypes of breast cancer treated with neoadjuvant chemotherapy. About 130 (56.3 %) patients received anthracycline-based, 56 (24.2 %) capecitabine-containing (CAX), 28 (12.1 %) taxotere and 17 (7.4 %) non-anthracycline-containing chemotherapy regimens at the Tomsk Cancer Research Institute between 2000 and 2010. Tumors were subtyped according to the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) immunohistochemical data. The majority of tumors (48.9 %) were ER+/PR+ and HER2-negative (HR+/HER2−), 10.4 % were ER+ PR+ and HER2-positive (HR+/HER2+), 9.1 % were ER−/PR− and HER2-overexpressed (HER2-enriched) and 31.6 % were ER-/PR- and HER2-negative (triple negative). Both cOR and pCR were significantly higher in the triple-negative tumors compared to the other subtypes ( P = 0.021 and P = 0.033, respectively). Among the four chemotherapy regimens, only CAX regimen had a predictive value for cOR (HR 2.30, 95 % CI 1.16-4.58, P = 0.009). Multivariate regression analysis showed that the triple-negative subtype (HR 2.54, 95 % CI 1.06-1.42, P = 0.011) and CAX regimen (HR 3.01, 95 % CI 1.01-1.46, P = 0.002) were significantly associated with cOR. No association between patient's PFS and a tumor subtype was observed. However, there was a trend for a prolonged PFS among patients with cOR ( P = 0.056). Our data indicate a potentially better prognosis for triple-negative breast cancer patients if treated with the CAX neoadjuvant regimen. [ABSTRACT FROM AUTHOR]