To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or ...both (THP), or monoclonal antibodies alone (HP).
Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation.
TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only.
The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.
Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in ...combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221).
Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).
Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.
Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.
Objectives
To clarify the clinical features preceding the onset of bipolar disorder (BD) has become a public health priority for the prevention of high morbidity and mortality. BD remains frequently ...under‐ or misdiagnosed, and under‐ or mistreated, often for years.
Methods
We assessed the predictive value of precursors and prodromes of BD. We assessed precursors of first‐lifetime manic or hypomanic episodes with/without mixed features in retrospective and prospective studies. The task force evaluated and summarized separately assessments of familial risk, premorbid personality traits, retrospective, and prospective studies.
Results
Cyclothymic features, a family history of BD, retrospectively reported attenuated manic symptoms, prospectively identified subthreshold symptoms of hypomania, recurrence of depression, panic anxiety and psychotic features, have been identified as clinical precursors of BD. The prodromal symptoms like hypomania often appears to be long enough to encourage early identification and timely intervention.
Conclusions
The predictive value of any risk factor identified remains largely unknown. Prospective controlled studies are urgently needed for prevention and effective treatment.
To evaluate the presence of affective signs and symptoms as precursors of bipolar disorder in prospective studies, including assessment of their prevalence, duration, and predictive value.
We ...followed PRISMA guidelines to search PubMed, CINAHL, PsycINFO, EMBASE, SCOPUS, and ISI Web of Science databases to May 31, 2013, using the terms bipolar disorder AND (antecedent* OR predict* OR prodrom* OR prospect*) AND (diagnosis OR development). Hand searching of identified reports led to additional relevant references.
We included only English-language articles containing (1) prospective, longitudinal studies with at least 2 structured clinical assessments (intake and follow-up); (2) no previous DSM-III or DSM-IV diagnoses of bipolar I or bipolar II; and (3) diagnostic outcome of bipolar I or bipolar II. Studies of subjects at familial risk of bipolar disorder were excluded, as these have been reviewed elsewhere.
We tabulated details of study design, outcomes, precursors, and predictive value. Only studies reporting a positive predictive association were included.
In 26 published reports meeting selection criteria, methods varied widely in terms of design, duration of follow-up, ages, and populations investigated. Despite such heterogeneity in methods, findings were notably consistent. Precursors of bipolar disorder include mood lability, subsyndromal and major depression, subsyndromal hypomanic symptoms with or without major depression, cyclothymia and bipolar not otherwise specified, major depression with psychotic features, and other psychotic disorders. Bipolar disorder was also predicted by juvenile onset of major depression as well as frequency and loading of hypomanic or depressive symptoms.
Despite the limitations of published reports, prospectively identified precursors of bipolar disorder typically arose years prior to syndromal onset, often with significant early morbidity and disability. Prospectively identified precursors of bipolar disorder are generally consistent with findings in retrospective and family-risk studies. Combining precursors and other risk factors may increase predictive value, support earlier diagnosis, improve treatment, and limit disability in bipolar disorder.
Adiposity may contribute to the future risk of disease. The aim of this study was to evaluate the accuracy and reliability of an air-displacement plethysmography (ADP) system to estimate percentage ...fat mass (%FM) in preterm infants and to evaluate interdevice reliability in infants.
A total of 70 preterm and 9 full-term infants were assessed. The accuracy of ADP measurements was assessed by determining reference %FM values using H(2)(18)O dilution measurement.
Mean %FM by ADP was 5.67 ± 1.84 and mean %FM by H(2)18O dilution was 5.99 ± 2.56. Regression analysis showed that %FM by ADP was associated with %FM by H(2)(18)O dilution (R2 = 0.63, SE of estimate (SEE) = 1.65, P = 0.006). Bland-Altman analysis showed no bias (r = -0.48, P = 0.16) and 95% limits of agreement were -3.40 to 2.76 %FM. There was no difference in mean interdevice reliability %FM values (8.97 vs. 8.55 %FM) between ADP 1 and 2. Regression analysis indicated a low SEE (1.14% FM) and high R2 (0.91); 95% limits of agreement were -1.87 to 2.71 %FM. The regression line did not differ significantly from the line of identity.
ADP is a noninvasive, reliable, and accurate technique to measure preterm infants' body composition in both research and clinical settings.
Abstract Background Although Indocyanine green (ICG) is used to find sentinel nodes (SN) in patients with breast cancer (BC), its role in clinical practice is still debated, and needs a definitive ...validation to be included in the standard approach to finding sentinel nodes in breast cancer. Materials and methods To validate the ICG methods of detecting the SN in BC we have recently concluded a prospective validation trial. Patients with clinically node-negative, invasive early BC scheduled for breast surgery and SN biopsy were included in the trial. All the patients underwent SN detection using both the standard-of-care procedure using radioisotope technetium (99mTc) and the ICG, using the Photodynamic Eye camera. A comparison of the detection rate and the diagnostic accuracy of the two methods was performed to detect the equivalency of the two approaches. Results At the end of the enrolment, 301 patients were considered eligible and included in the trial, and 589 nodes were removed. Five hundred and eighty-three nodes (99%) were identified with ICG (median 2 nodes per patient) and 452 (76.7%) were identified with 99mTc (median 2 nodes per patient). A concordance index of 98.75% (CI, 95% = 97.1%–99.5%) was detected. The dosage given ranged from 0.3 to 1.4 ml. ICG was used in all patients eligible for SN biopsy without any significant acute side effects. Conclusions The index of concordance between 99mTc and ICG seems to be extremely high, suggesting that ICG could be validated as an alternative method to 99mTc in the detection of SN in BC.
The newly introduced Mixed Features Specifier of Major Depressive Episode and Disorder (MDE/MDD) is especially challenging in terms of pharmacological management. Prior to the publication of the ...Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the symptoms of the mixed features specifier were intradepressive hypomanic symptoms, always and only associated with bipolar disorder (BD). Intradepressive hypomanic symptoms, mostly referred to as depressive mixed states (DMX), have been poorly characterized, and their treatment offers significant challenges. To understand the diagnostic context of DMX, we trace the nosological changes and collocation of intradepressive hypomanic symptoms, and examine diagnostic and prognostic implications of such mixed features. One of the reasons so little is known about the treatment of DMX is that depressed patients with rapid cycling, substance abuse disorder, and suicidal ideation/attempts are routinely excluded from clinical trials of antidepressants. The exclusion of DMX patients from clinical trials has prevented an assessment of the safety and tolerability of short- and long-term use of antidepressants. Therefore, the generalization of data obtained in clinical trials for unipolar depression to patients with intradepressive hypomanic features is inappropriate and methodologically flawed. A selective review of the literature shows that antidepressants alone have limited efficacy in DMX, but they have the potential to induce, maintain, or worsen mixed features during depressive episodes in BD. On the other hand, preliminary evidence supports the effective use of some atypical antipsychotics in the treatment of DMX.
After participating in this activity, learners should be better able to:• Evaluate factors that have been identified in prospective studies as predicting the onset of bipolar disorder ABSTRACT: The ...prodromal phase of bipolar disorder (BD) remains incompletely characterized, limiting early detection of BD and delaying interventions that might limit future morbidity and disability. Retrospective and family-risk studies have consistently found evidence of prodromal psychopathology in subjects later diagnosed with BD. Here, we review prospective studies of clinical risk factors and exposures identified before diagnosis of BD: our findings are consistent with those from retrospective and family-risk studies. Affective psychopathology often precedes diagnosis to suggest a homotypic trajectory in developing BD. Early non-affective (heterotypic) psychopathological disturbances, including anxiety and disruptive behavior disorders, as well as environmental factors and exposures, have been found in prospective studies to increase the risk of BD, but tend to lack specificity in predicting BD. Findings from prospective studies are encouragingly similar to those of retrospective and family-risk studies.
Abstract Background Early phases and suspected precursor states of bipolar disorder are not well characterized. We evaluate the prevalence, duration, clinical features and predictive value of ...non-affective psychopathology as clinical risk factors for bipolar disorder in prospective studies. Methods We screened PubMed, CINAHL, PsycINFO, Embase, SCOPUS, and ISI-Web of Science databases from inception up to January 31, 2014, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and searched: bipolar disorder AND antecedent⁎ OR predict⁎ OR prodrom⁎ OR prospect⁎ OR risk⁎ AND diagnosis OR development. We included only English language reports on prospective, longitudinal studies with two structured clinical assessments (intake and follow-up); no DSM intake diagnosis of bipolar-I or -II; diagnostic outcome was bipolar-I or -II. Details of study design, risk factors, and predictive value were tabulated. Results We found 16 published reports meeting selection criteria, with varying study design. Despite heterogeneity in methods, findings across studies were consistent. Clinical risk factors of bipolar disorder were early-onset panic attacks and disorder, separation anxiety and generalized anxiety disorders, conduct symptoms and disorder, ADHD, impulsivity and criminal behavior. Limitations Since risk factors identified in some prospective studies are predictive of other conditions besides bipolar disorder, these preliminary findings require replication, and their sensitivity, specificity and predictive value need to be assessed. Conclusions Clinical risk factors for bipolar disorder typically arise years prior to syndromal onset, include anxiety and behavioral disorders with unclear sensitivity and specificity. Prospectively identified clinical risk factors for bipolar disorder are consistent with retrospective and family-risk studies. Combining clinical risk factors with precursors and family-risk may improve early identification and timely and appropriate treatment of bipolar disorder.
Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with ...newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns.
Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern.
Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039).
Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.
•Many young women desire future biologic children after breast cancer.•Sixty-four percent of study patients had fertility concerns.•A low proportion of patients took fertility preservation measures.•Women treated with chemotherapy reported greater physical and sexual difficulties.•Women with stable relationships reported less psychosocial problems than single women.
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