Abstract Background The role of environmental risk factors in the development of bipolar disorder (BD) is not well characterized. We evaluate the prevalence, duration, and predictive value of ...environmental exposures for BD in longitudinal studies. Methods We conducted a systematic search of PubMed, Scopus and PsychINFO databases until April 01, 2015, using the following words in combination: prenatal exposure; maternal exposure; trauma; childhood abuse; alcoholism; cannabis; smoking; cocaine; central stimulants; opioids; uv light; pollution; global warming; vitamin d AND bipolar disorder. Additional references were obtained through cross-referencing. We included (1) longitudinal cohort studies or case-control studies nested within longitudinal designs; (2) studies of subjects without lifetime BD diagnoses at initial assessment and a diagnosis of BD at follow-up by clinical or structured assessment. Familial-risk studies were excluded. We tabulated details of study-design, exposure, diagnostic criteria, risk of bipolar disorder expressed as odd ratio (OR), relative risk (RR) or hazard ratio (HR). Results Of 2119 studies found, 22 met inclusion criteria. Risk factors identified can be grouped in 3 clusters: neurodevelopment (maternal influenza during pregnancy; indicators of fetal development), substances (cannabis, cocaine, other drugs – opioids, tranquilizers, stimulants, sedatives), physical/psychological stress (parental loss, adversities, abuses, brain injury). Limitations Heterogeneity of designs and methodology prevented the use of meta-analysis of the findings; studies did not provide sensitivity, specificity and predictive value of the risk factors identified; case-control studies classify cases based on diagnostic membership, but do not control for familial or genetic liability; methods for determining the exposures varied among studies. Conclusion Only preliminary evidence exists that exposure to viral infection, substances or trauma increase the likelihood of BD. Given the limited data available, the specificity, sensitivity and predictive value could not be computed. As exposures are sometimes amenable to prevention, further research is needed.
Purpose
To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC).
Methods
Non-diabetic women with HER2-negative MBC were randomized ...to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m
2
+ cyclophosphamide (C) 600 mg/m
2
× 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS).
Results
One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range IQR 24.6–50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8–10.4) in arm A and 9.9 (95% CI 7.4–11.5) in arm B (
P
= 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6–11.7) versus 8.5 (95% CI 5.8–9.7) in those with HOMA index ≥ 2.5 (
P
= 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (
P
= 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS.
Conclusions
The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.
High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need ...of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy.
Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population.
The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab 44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab.
The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way.
•Atezolizumab with neoadjuvant carboplatin/nab-paclitaxel led to non-significantly higher pCR rate in PD-L1+ TNBC.•In other trials neoadjuvant ICIs and chemotherapy significantly improved pCR rate, but EFS was independent of pCR.•Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC.•Lack of pCR improvement may be misleading as to the impact of atezolizumab on long-term efficacy in high risk TNBC.
Abstract Objectives Compare reported rates of mood-shifts from major depression to mania/hypomania/mixed-states during antidepressant (AD)-treatment and rates of diagnostic change from major ...depressive disorder (MDD) to bipolar disorder (BPD). Methods Searching computerized literature databases, followed by summary analyses. Results In 51 reports of patients diagnosed with MDD and treated with an AD, the overall risk of mood-switching was 8.18% (7837/95,786) within 2.39±2.99 years of treatment, or 3.42 (95% CI: 3.34–3.50) %/year. Risk was 2.6 (CI: 2.5–2.8) times greater with/without AD-treatment by meta-analysis of 10 controlled trials. Risk increased with time up to 24 months of treatment, with no secular change (1968–2012). Incidence rates were 4.5 (CI: 4.1–4.8)-times greater among juveniles than adults (5.62/1.26 %/year; p <0.0001). In 12 studies the overall rate of new BPD-diagnoses was 3.29% (1928/56,754) within 5.38 years (0.61 0.58–0.64 %/year), or 5.6-times lower (3.42/0.61) than annualized rates of mood-switching. Conclusions AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain. Limitations Rates and definitions of mood-switching with ADs varied greatly, exposure-times rarely were precisely defined, and there was little information on predictive associations between mood-switches and BPD-diagnosis.
Patients with borderline (BL) or locally advanced (LA) pancreatic adenocarcinoma are usually treated with primary chemotherapy (CT), followed by resection when feasible. Scanty data are available ...about the criteria to candidate patients to resection after CT.
Between 2002 and 2016 overall 223 patients diagnosed with BL or LA pancreatic adenocarcinoma were primarily treated with Gemcitabine combination (4-drugs or nab-paclitaxel-gemcitabine) for 3–6months followed by surgery and/or chemoradiation. Resection was carried out when radical resection could be predicted by imaging studies and intraoperative findings. The prognostic value of both pre-treatment factors and treatment response was retrospectively evaluated, searching for criteria that could improve the selection of patients for surgery.
Median survival (MS) for the whole population was 18.3months. Surgical resection was carried out in 61 patients; MS in resected patients was significantly longer (30.0months) as compared with 162 non-resected patients (16.5months) (P<0.00001). According to response criteria, 48% had a radiological partial response, 47% a stable disease and 5% a disease progression); CA19.9 response (reduction>50%) was obtained in 77.8% of patients. Among resected patients, neither pre-treatment factors, including BL/LA distinction, nor radiological response, were able to prognosticate survival differences. Survival of resected patients having no CA19.9 response was significantly lower as compared with responders (MS 15.0 versus 31.5months,P=0.04), and was similar to non-responders patients that did not undergo resection (MS 10.9months,P=0.25). Multivariate analysis carried out on the overall population, showed that Karnofsky performance status, T3–T4 status, resection and CA19.9 response were independent prognostic factors, while radiological response, BL/LA distinction and baseline CA19.9 had not significant influence on survival.
CA19.9 response may allow a better selection of patients who will benefit from resection after primary CT for BL or LA pancreatic adenocarcinoma.
The aim of this study was to meta-analyze the prevalence of symptoms before an initial mood episode of bipolar disorder (BD) and the prevalence of subthreshold symptoms before a BD mood episode ...recurrence, to facilitate early identification and prevention.
Systematic literature reviews were conducted in PsycINFO and PubMed for prospective or retrospective studies reporting on the prevalence and longest duration of symptoms before an initial or recurrent mood episode of BD. Random effects meta-regression explored whether geographic location, age, percentage of female individuals, and study quality moderated the overall prevalence.
In 11 studies (n = 1,078), the prodrome preceding an initial mood episode lasted 27.1 ± 23.1 months (range, 4.6-130 months). In 10 studies (n = 1,000), the subthreshold symptoms preceding a recurrent mood episode lasted 1.0 ± 0.9 months (range, 0.5-1.3 months). The most common symptoms were largely consistent with diagnostic criteria symptoms associated with the subsequent mood polarity for both the initial prodrome and the period prior to a recurrent mood episode. Few moderators of symptom prevalences emerged, and significant heterogeneity remained.
The initial prodromal period is sufficiently long and characterized by symptoms of the subsequent mood episode to make early identification and intervention programs feasible. Conversely, the period of subthreshold symptoms before a recurrent mood episode is short, mandating adequate psychoeducation of patients and families, monitoring of changes in sleep and activity, plus sufficiently frequent follow-up visits to identify patients before a mood episode recurrence. Future prospective investigations, designed to address the identified shortcomings in the extant literature, are needed to identify more clinically applicable information.
Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) are neurodevelopmental disorders with onset in childhood and early adolescence, and common persistence in adulthood. Both ...disorders are often undiagnosed, misdiagnosed, and sometimes over diagnosed, leading to high rates of morbidity and disability. The differentiation of these conditions is based on their clinical features, comorbidity, psychiatric family history course of illness, and response to treatment. We review recent relevant findings and highlight epidemiological, clinical, family history, course, and treatment-response differences that can aid the differential diagnosis of these conditions in an outpatient pediatric setting.
Background
Distinguishing pediatric bipolar disorder (BD) from attention‐deficit hyperactivity disorder (ADHD) can be challenging. Hyperactivity is a core feature of both disorders, but severely ...disturbed sleep and circadian dysregulation are more characteristic of BD, at least in adults. We tested the hypothesis that objective measures of activity, sleep, and circadian rhythms would help differentiate pediatric subjects with BD from ADHD and typically developing controls.
Methods
Unmedicated youths (N = 155, 97 males, age 5–18) were diagnosed using DSM‐IV criteria with Kiddie‐SADS PL/E. BD youths (n = 48) were compared to typically developing controls (n = 42) and children with ADHD (n = 44) or ADHD plus comorbid depressive disorders (n = 21). Three‐to‐five days of minute‐to‐minute belt‐worn actigraph data (Ambulatory Monitoring Inc.), collected during the school week, were processed to yield 28 metrics per subject, and assessed for group differences with analysis of covariance. Cross‐validated machine learning algorithms were used to determine the predictive accuracy of a four‐parameter model, with measures reflecting sleep, hyperactivity, and circadian dysregulation, plus Indic's bipolar vulnerability index (VI).
Results
There were prominent group differences in several activity measures, notably mean 5 lowest hours of activity, skewness of diurnal activity, relative circadian amplitude, and VI. A predictive support vector machine model discriminated bipolar from non‐bipolar with mean accuracy of 83.1 ± 5.4%, ROC area of 0.781 ± 0.071, kappa of 0.587 ± 0.136, specificity of 91.7 ± 5.3%, and sensitivity of 64.4 ± 13.6%.
Conclusions
Objective measures of sleep, circadian rhythmicity, and hyperactivity were abnormal in BD. Wearable sensor technology may provide bio‐behavioral markers that can help differentiate children with BD from ADHD and healthy controls.
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