Immunostimulatory and anti-tumor metronomic cyclophosphamide regimens assessed in primary orthotopic and metastatic murine breast cancer.

The impressive successes of immune checkpoint blockade antibodies to treat various types of cancer are limited to minor subsets of patients. Combination therapy strategies, including with chemotherapy, are being explored to possibly improve the efficacy of immunotherapies. Here we report results regarding the use of an immunostimulatory regimen of metronomic cyclophosphamide (CTX). We show that in orthotopic models of syngeneic murine triple-negative breast cancer (EMT6), CTX administered at 140 mg/kg every 6 days (CTX140 1q6d) is superior at inhibiting primary tumor growth when compared to maximum tolerated dose or daily oral (continuous) low-dose CTX. In SCID or SCID beige mice, anti-tumor effects of CTX140 1q6d are reduced, reinforcing the therapeutic contribution of the adaptive and innate immune systems. In a second breast cancer model (SP1-AC2M2), CTX140 1q6d again showed clear superiority in anti-tumor effects, causing complete tumor regressions; however, these mice were not protected from subsequent tumor re-challenge, suggesting absence of immune memory. We also show that in an aggressive and metastatic cisplatin-resistant variant (EMT6-CDDP), CTX140 1q6d is superior and invokes an influx of intra-tumoral CD4+ and CD8+ T cells. CTX increases expression of tumor cell PD-L1; however, when combined with concomitant PD-L1 antibody therapy none of the CTX regimens showed increased benefit. This work sheds light on the potential use of metronomic CTX for the treatment of breast cancer, in particular using the quasi-weekly regimen, but also underscores the complexity of the anti-tumor mechanisms and potential to improve immune checkpoint therapy efficacy.

Therapeutic impact of Nintedanib with paclitaxel and/or a PD-L1 antibody in preclinical models of orthotopic primary or metastatic triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, in part because of the current lack of any approved molecularly targeted therapy. We evaluated various combinations of three different drugs: nintedanib, an antiangiogenic TKI targeting VEGF receptors, paclitaxel (PTX), or a PD-L1 antibody, using models of orthotopic primary or advanced metastatic TNBC involving a metastatic variant of the MDA-MB-231 human cell line (called LM2-4) in SCID mice and two mouse lines (EMT-6 and a drug-resistant variant, EMT-6/CDDP) in immunocompetent mice. These drugs were selected based on the following: PTX is approved for TNBC; nintedanib combined with docetaxel has shown phase III clinical trial success, albeit in NSCLC; VEGF can act as local immunosuppressive factor; and PD-L1 antibody plus taxane therapy was recently reported to have encouraging phase III trial benefit in TNBC. METHODS: Statistical analyses were performed with ANOVA followed by Tukey's Multiple Comparison Test or with Kruskal-Wallis test followed by Dunn's Multiple Comparison Test. Survival curves were analyzed using a Log-rank (Mantel Cox) test. Differences were considered statistically significant when p values were < 0.05. RESULTS: Toxicity analyses showed that nintedanib is well tolerated when administered 5-days ON 2-days OFF; PTX toxicity differed in mice, varied with cell lines used and may have influenced median survival in the metastatic EMT6/CDDP model; while toxicity of PD-L1 therapy depended on the cell lines and treatment settings tested. In the LM2-4 system, combining nintedanib with PTX enhanced overall antitumor efficacy in both primary and metastatic treatment settings. In immunocompetent mice, combining nintedanib or PTX with the PD-L1 antibody improved overall antitumor efficacy. Using the advanced metastatic EMT-6/CDDP model, optimal efficacy results were obtained using the triple combination. CONCLUSIONS: These results suggest circumstances where nintedanib plus PTX may be potentially effective in treating TNBC, and nintedanib with PTX may improve PD-L1 therapy of metastatic TNBC.

Pre- and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro- or macro-metastatic disease.

BACKGROUND: There are phase 3 clinical trials underway evaluating anti-PD-L1 antibodies as adjuvant (postoperative) monotherapies for resectable renal cell carcinoma (RCC) and triple-negative breast cancer (TNBC); in combination with antiangiogenic VEGF/VEGFR2 inhibitors (e.g., bevacizumab and sunitinib) for metastatic RCC; and in combination with chemotherapeutics as neoadjuvant (preoperative) therapies for resectable TNBC. METHODS: This study investigated these and similar clinically relevant drug combinations in highly translational preclinical models of micro- and macro-metastatic disease that spontaneously develop after surgical resection of primary kidney or breast tumours derived from orthotopic implantation of murine cancer cell lines (RENCAluc or EMT-6/CDDP, respectively). RESULTS: In the RENCAluc model, adjuvant sunitinib plus anti-PD-L1 improved overall survival compared to either drug alone, while the same combination was ineffective as early therapy for unresected primary tumours or late-stage therapy for advanced metastatic disease. In the EMT-6/CDDP model, anti-PD-L1 was highly effective as an adjuvant monotherapy, while its combination with paclitaxel chemotherapy (with or without anti-VEGF) was most effective as a neoadjuvant therapy. CONCLUSIONS: Our preclinical data suggest that anti-PD-L1 plus sunitinib may warrant further investigation as an adjuvant therapy for RCC, while anti-PD-L1 may be improved by combining with chemotherapy in the neoadjuvant but not the adjuvant setting of treating breast cancer.

Impact of Chemical-Induced Mutational Load Increase on Immune Checkpoint Therapy in Poorly Responsive Murine Tumors.

A recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26, and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Although tumor PD-L1 expression was upregulated in in vivo chemotherapy-exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically "hot" or "cold" tumors with a high mutational load, to which certain chemotherapy agents may contribute, on immunotherapy outcomes. Mol Cancer Ther; 17(4); 869-82. ©2018 AACR.

A compromise solution between overlapping and overlooking DSM personality disorders in Chinese psychiatric practice.

OBJECTIVE: This study aimed to examine the overlaps between the Diagnostic and Statistical Manual-5 (DSM-5) Personality Disorders (PDs) in a high-risk clinical population and to explore a transitional model for implementing DSM-5 PDs. METHOD: A sample population of 982 outpatients with at least one diagnosed PD was selected from 3,075 outpatients of the Shanghai Mental Health Center. The diagnostic process comprised of a personality diagnostic questionnaire and a structured clinical interview. RESULTS: 685 (22.3%) patients were diagnosed with at least one of six PDs (antisocial, avoidant, borderline, narcissistic, obsessive-compulsive, and schizotypal) under the alternative DSM-5 model for personality disorders proposed in Section III of the DSM-5. Nearly 20.3% of the subjects with PD met criteria for at least two PDs (of the 685 PD patients/6 PD model). Cluster and principal component analyses suggest a transitional model for the 7 specific PD categories (among the 722 PD patients, the overlapping rate was 24.1%) will be more appropriate for PD diagnosis in China. CONCLUSIONS: Using the simplified PD categories in the alternative DSM-5 model for personality disorders will reduce the overlaps in PD diagnoses in Chinese psychiatric practice, and should be preferred over the DSM-5 PD diagnostic system.

Progressive decline of cognition during the conversion from prodrome to psychosis with a characteristic pattern of the theory of mind compensated by neurocognition.

The association between neurocognition and the theory of mind (ToM) abilities during the progression of psychosis is unclear. This study included 83 individuals with attenuated psychosis syndrome (APS), from which 26 converted to psychosis (converters) after a follow up period of 18months. Comprehensive cognitive tests (including MATRICS Consensus Cognitive Battery, Faux-Pas Task, and Reading-Mind-in-Eyes Tasks) were administered at baseline. A structural equation modeling (SEM) analysis was conducted to estimate the effects of neurocognition on the ToM functioning in both APS and healthy controls (HC) datasets. At baseline, the converters and non-converters groups differed significantly on several domains of cognitive performance. The SEM analysis demonstrated that the path from neurocognition to ToM was statistically significant in the APS dataset (p<0.001). However, in the HC dataset, the result of the same analysis was not significant (p=0.117). Positive correlations between neurocognition and ToM were observed, and the most obvious correlations were found in the converters group compared with the non-converters group (p=0.064) and compared with the HC group (p=0.002). The correlation between ToM abilities and neurocognition may be increased during the progression of the condition, especially for individuals who convert to psychosis after a short period.

Correlation of social cognition and neurocognition on psychotic outcome: a naturalistic follow-up study of subjects with attenuated psychosis syndrome.

Neurocognitive decline has been observed in patients with psychosis as well as attenuated psychosis syndrome (APS). We tested the hypothesis that APS increases dependence on neurocognition during the interpretation of others' mental states and that a combination index of Theory of Mind (ToM) and neurocognition improves the predictive accuracy of psychosis conversion. A sample of 83 APS individuals and 90 healthy controls (HC) were assessed by comprehensive cognitive tests. The cohort also completed a one-year follow-up. In the APS group, ToM was associated with an apparent increase in neurocognition, but this trend was not evident in the HC group. Using the new index of combined neurocognition and ToM scores, the sensitivity for predicting psychosis-proneness was 75% and the specificity was 69%. Our data suggest that the correlations between ToM function and neurocognition in APS subjects were stronger than those in healthy controls. A composite index of neurocognition and ToM could improve the predictive validity of a future conversion to psychosis.

Efficacy of Cotargeting Angiopoietin-2 and the VEGF Pathway in the Adjuvant Postsurgical Setting for Early Breast, Colorectal, and Renal Cancers.

Antiangiogenic tyrosine kinase inhibitors (TKI) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III clinical trials. Angiopoietin-2 (Ang2) is a proangiogenic and proinflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models. In the MDA-MB-231.LM2-4 human breast cancer model, adjuvant sunitinib was ineffective, whereas adjuvant CVX-060 delayed the progression of pulmonary or distant lymphatic metastases; however, overall survival was only improved with the adjuvant use of a VEGF-A/Ang2-bispecific CovX-body (CVX-241) but not when CVX-060 is combined with sunitinib. Adjuvant CVX-241 also showed promise in the EMT-6/CDDP murine breast cancer model, with or without an immune checkpoint inhibitor (anti-PD-L1). In the RENCA model of mouse renal cancer, however, combining CVX-060 with sunitinib in the adjuvant setting was superior to CVX-241 as treatment for postsurgical lung metastases. In the HCT116 and HT29 xenograft models of colorectal cancer, both CVX-060 and regorafenib inhibited liver metastases. Overall, our preclinical findings suggest differential strategies by which Ang2 blockers can be successfully combined with VEGF pathway targeting in the adjuvant setting to treat micrometastatic disease-particularly, in combination with VEGF-A blockers (but not VEGFR2 TKIs) in resected breast cancer; in combination with VEGFR2 TKIs in resected kidney cancer; and as single agents or with VEGFR2 TKIs in resected colorectal cancer. Cancer Res; 76(23); 6988-7000. ©2016 AACR.

Co-morbidity of personality disorder in schizophrenia among psychiatric outpatients in China: data from epidemiologic survey in a clinical population.

BACKGROUND: The reported rates of personality disorder (PD) in subjects with schizophrenia (SZ) are quite varied across different countries, and less is known about the heterogeneity of PD among subjects with SZ. We examined the co-morbidity of PD among patients who are in the stable phase of SZ. METHOD: 850 subjects were randomly sampled from patients diagnosed with SZ in psychiatric and psycho-counseling clinics at Shanghai Mental Health Center. Co-morbidity of PDs was assessed through preliminary screening and patients were administered several modules of the SCID-II. Evidence of heterogeneity was evaluated by comparing patients diagnosed with SZ with those who presented with either affective disorder or neurosis (ADN). RESULTS: 204 outpatients (24.0 %) in the stable phase of SZ met criteria for at least one type of DSM-IV PD. There was a higher prevalence of Cluster-A (odd and eccentric PD) and C (anxious and panic PD) PDs in SZ (around 12.0 %). The most prevalent PD was the paranoid subtype (7.65 %). Subjects with SZ were significantly more likely to have schizotypal PD (4.4 % vs. 2.1 %, p = 0.003) and paranoid PD (7.6 % vs. 5.4 %, p = 0.034), but much less likely to have borderline, obsessive-compulsive, depressive, narcissistic and histrionic PD. CONCLUSIONS: These findings suggest that DSM-IV PD is common in patients with SZ than in the general population. Patterns of co-morbidity with PDs in SZ are different from ADN.

Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle-Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer.

VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR.

Theory of Mind Impairments in Youth at Clinical High Risk of Psychosis.

OBJECTIVE: The normal maturational processes of theory of mind (ToM) capacity are ongoing during adolescence and even early adulthood. However, research has shown that ToM ability also declines among adults suffering from prodromal psychotic experiences. The goal of this study was to investigate the characteristics of ToM performance in youth with clinical high risk (CHR) of psychosis. METHODS: The Reading Mind in Eyes Task (RMET), including own-race and other-race eyes, was administered to 40 CHR youth; 42 age-, gender-, and education-matched healthy controls (HCs); and 62 adult patients with schizophrenia (SZ). Nine-month follow-up data were collected from 31 CHR subjects, of whom 7 (22.6%) had made the transition to psychosis. RESULTS: CHR youth showed significant impairment in RMET performance compared to HC youth but performed better than did SZ patients. Moreover, they were significantly slower than were HC youth in responding to the RMET, with a response time similar to that of SZ patients. In particular, they had significantly poorer accuracy in interpreting positive and neutral eye expressions compared to the HC group, but not in interpreting negative eye expressions. Preliminary follow-up data showed a trend toward significance (p = 0.079) for RMET performance between those who transitioned to psychosis and those who did not. CONCLUSIONS: Our findings illustrate that deficits in ToM capacity, specifically the ability to interpret people's mental state from eye expressions, occur early on in prodromal psychosis in youth. Early interventions for CHR youth focusing on ToM enhancement may halt progress toward psychosis.

Faux pas recognition performance in a help-seeking population at clinical high risk of psychosis.

There is a growing body of evidence suggesting that patients with psychosis show impaired theory of mind (ToM). However, much remains to be understood as to whether ToM deficits occur in the premorbid or post-onset period of psychosis. Our primary aim was to examine empirically impairment on ToM tasks in a group of individuals with clinical high risk (CHR) of psychosis. Fifty CHR participants identified through the Structured Interview for Prodromal Syndromes and 52 age-/education-matched controls were assessed with a complete standard neuropsychological battery (the MCCB, MATRICS Consensus Cognitive Battery) and a social cognition assessment (Faux Pas Test, FPT). We then examined the association of baseline FPT performance with conversion to psychosis at 12-month follow-up. Compared with controls, the CHR group showed significantly poorer performances on the FPT and most MCCB domains. Significant positive correlations were found between faux pas detection and the MCCB domains of Attention/Vigilance and Working Memory in CHR participants when controlling for age and years of education. Mean scores on the FPT in 14 converters who were diagnosed with full-blown psychosis within 12 months were significantly lower than they were for non-converters. Impairments in ToM ability are acquired earlier in the prodromal stage of psychosis, along with general cognition (such as memory function) deficits. Declines in ToM ability may overlap with the progress of psychosis (the gradual loss insight), sharing similar neural substrates, and reflected by impairments in basic cognitive function.

Temsirolimus Maintenance Therapy After Docetaxel Induction in Castration-Resistant Prostate Cancer.

LESSONS LEARNED: Temsirolimus maintenance therapy after docetaxel induction chemotherapyis safe in patients with castration-resistant prostate cancer, although biochemical or tumor responses are rare;does not diminish quality of life; anddelays radiological and/or symptomatic progression by approximately 6 months. BACKGROUND: No standard therapy is available for men with castration-resistant prostate cancer (CRPC) who have responded to docetaxel and do not yet have disease progression. Hence, we designed a single-arm phase II trial to explore whether the mTOR inhibitor temsirolimus can maintain the response to docetaxel without compromising quality of life. METHODS: After successful docetaxel induction (75 mg/m(2) every 3 weeks; 6-10 cycles), 21 CRPC patients underwent temsirolimus maintenance treatment (25 mg weekly; 4 weeks per cycle). The primary endpoint was the time to treatment failure (TTTF) (i.e., radiological and/or symptomatic progression). The secondary endpoints included the tumor response rate (RECIST 1.0), safety (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0), quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P]), pain (Present Pain Intensity [PPI] scale), prostate-specific antigen (PSA) parameters, including time to PSA progression (TTPP) according to Prostate Cancer Clinical Trials Working Group criteria, and serial enumeration of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs). RESULTS: Patients received a median of 7 cycles of temsirolimus (range, 1-28), resulting in a median TTTF of 24.3 weeks (95% confidence interval [CI], 16.1-33.0), 1 partial tumor response (4.8%), 1 PSA response (4.8%), and a median TTPP of 12.2 weeks (95% CI, 7.8-23.9). Grade 3-4 adverse events were infrequent, and FACT-P and PPI scores remained stable during treatment. CECs did not predict clinical benefit, and CEPs were not consistently detectable. CONCLUSION: Temsirolimus maintenance therapy after successful docetaxel induction is feasible, does not adversely affect quality of life, and, in this exploratory single-arm phase II study, resulted in a median TTTF of 24.3 weeks.

Interaction of social role functioning and coping in people with recent-onset attenuated psychotic symptoms: a case study of three Chinese women at clinical high risk for psychosis.

Clinical high risk of psychosis is defined as the period in which the first signs of psychotic symptoms begin to appear. During this period, there is an increased probability of developing frank psychosis. It is crucial to investigate the interaction between psychotic symptoms and the individual's personality and life experiences in order to effectively prevent, or delay the development of psychosis. This paper presents case reports of three Chinese female subjects with attenuated positive symptoms, attending their initial outpatient assessment in a mental health service, and their longitudinal clinical outcomes. Information regarding each subject's symptoms and life stressors was collected at 2-month intervals over a 6-month period. The assessments indicated that these women were suffering from the recent onset of symptoms in different ways. However, all three hid their symptoms from others in their school or workplace, and experienced a decline in performance related to their social roles and in their daily functioning. They were often excluded from the social groups to which they had previously belonged. A decline in social activities may be a risk factor in the development of psychosis and a mediator of functional sequelae in psychosis. Effective treatment strategies may include those that teach individuals to gain insights related to their symptoms and a service that provides a context in which individuals can discuss their psychotic symptoms.

Screening schizotypal personality disorder for detection of clinical high risk of psychosis in Chinese mental health services.

Schizotypal personality disorder (SPD) is viewed as a marker of prodromal psychosis. However, information regarding genetic risk (e.g. SPD) is often overlooked in the identification process. This study assessed whether SPD screening questionnaire help the prodromal psychosis (also widely applied "clinical high risk" (CHR) for clinical sample) detection in Chinese mental health service. This work also examined whether SPD had higher frequency in genetic risk population and CHR subjects. Two wave studies concerning the SPD identification was used for analysis. Wave 1 survey: 3075 subjects were assessed by Personality Diagnostic Questionnaire for SPD (PDQ-SPD) and Structured Clinical Interview for DSM-IV Axis II (SCID-II). Wave 2 survey: 2113 subjects screened with the prodromal questionnaire -brief version (PQ-B), PDQ-SPD, and interviewed by Structured Interview for Prodromal Symptoms (SIPS). Subjects with family history of mental disorders or with psychosis reported significantly higher scores in SPD. Receiver operating characteristic curves suggested that PDQ-SPD had moderate sensitivity and specificity for identifying CHR subjects. There was significant higher on SPD features in subjects with early stage (Course less than 1 year) of psychosis. Identifying SPD may be useful in early detection of psychosis especially in detecting the genetic risk syndromes and can be integrated with existing prodromal screen tools to improve its efficiency.

Neuropsychological Impairment in Prodromal, First-Episode, and Chronic Psychosis: Assessing RBANS Performance.

BACKGROUND: Cognitive deficits are observed throughout all developmental phases of psychosis. However, prior studies have usually focused on a limited illness period and used a wide variety of cognitive instruments. Therefore, it has been difficult to characterize or highlight cognitive functioning in different stages of psychosis. METHOD: We administered the RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) tests to 4 participant subgroups, including healthy volunteers (controls, HC, n = 28), subjects at high risk for clinical psychosis (prodrome, CHR, n = 27), first-episode schizophrenia patients (FE-Sz, n = 26), and mid-term and long-term chronic schizophrenia patients (Ch-Sz, n =147). Comparison, correlation, and regression analyses of RBANS index scores were assessed among groups. We examined clinical outcomes over 2 years between the CHR and HC subjects, and RBANS domains were used as possible predictors for conversion to psychosis. RESULTS: Performance on all RBANS domains was significantly impaired during a post-onset stage of psychosis (FE-Sz and Ch-Sz), and RBANS scores declined along with disease progression. Regression analyses showed that for CHR and HC subjects, baseline impairment in delayed memory (DM) significantly predicted conversion to psychosis. Additionally, partial correlations showed that for FE-Sz and Ch-Sz subjects, DM was the only correlate with a later stage of psychosis. CONCLUSIONS: Cognitive deficits broadly emerged, and diminished functioning followed along with disease progression. Impairment in DM is perhaps one domain that helps us understand the development of psychosis. A critical need is to monitor and treat memory functioning for psychotic patients throughout all phases of the disease.

FGF23: mediator of poor prognosis in a sizeable subgroup of patients with castration-resistant prostate cancer presenting with severe hypophosphatemia?

Castration-resistant prostate cancer (CRPC) is an advanced and incurable stage of the second most frequently diagnosed malignancy in men globally. Current treatment options improve survival modestly but eventually fail due to intrinsic or acquired therapeutic resistance. A hypothesis is presented wherein circulating levels of fibroblast growth factor 23 (FGF23), an endocrine member of the fibroblast growth factor family with phosphaturic properties, are proposed as a prognostic and predictive marker to identify CRPC patients with poor prognosis that are amenable to FGF23 antibody therapy (FGF23i) or treatment with fibroblast growth factor receptor inhibitors (FGFRi). With respect to the latter, FGF23 may also serve as a pharmacodynamic marker enabling individualized FGFRi dosing. We recently discovered that the development of severe and sustained hypophosphatemia in CRPC patients undergoing zoledronic acid therapy for bone metastases was associated with markedly worse prognosis compared to patients without or with only mild and transient hypophosphatemia. Severe hypophosphatemia is a typical manifestation of tumor-induced hypophosphatemic osteomalacia (TIO), a paraneoplastic condition mediated by FGF23 overexpression in most instances. While the postulated tumor-promoting role of FGF23 in CRPC or other malignancies has not yet been studied, several lines of evidence suggest that FGF23 may mediate both severe hypophosphatemia (via its endocrine properties) and aggressive CRPC behavior (via autocrine and paracrine activities): (i) FGF23 and the necessary signalling machinery (i.e. members of the fibroblast growth factor receptor [FGFR] family and the essential co-receptor α-KLOTHO [KL]) are highly expressed in a sizeable subgroup of CRPC patients; (ii) FGF/FGFR signalling plays important roles in prostate cancer; (iii) FGF23 can induce its own expression via a positive autocrine feedback loop involving FGFR1; and (iv) this positive feedback loop may be triggered by bone-targeted therapies frequently used for the treatment of CRPC-associated bone metastases. While there is a lack of personalized treatment strategies in the management of CRPC to date, FGF23 targeted therapy has the potential to fill this unmet clinical need in the not-so-distant future. In fact, FGFRi are currently in advanced clinical testing for a number of malignancies such as kidney and lung cancer, but there is a lack of conclusive data on FGFRi therapy in patients selected for FGF/FGFR pathway activation.

Prodromal psychosis detection in a counseling center population in China: an epidemiological and clinical study.

BACKGROUND: To investigate through a two-stage clinic-based screening, the frequency and clinical features of risk for psychosis syndromes in a Chinese help-seeking sample. METHOD: 2101 consecutive new patients ages 15-45 were recruited at their first visit to the Shanghai Mental Health Center (SMHC) and screened with the Prodromal Questionnaire-Brief version (PQ-B) and questions about genetic risk. The Structured Interview for Prodromal Syndromes (SIPS) was administered to a sub-sample to estimate rates of psychosis and clinical high risk (CHR) for psychosis syndromes. RESULTS: The frequency estimate of CHR syndromes in the total sample was 4.2%. Among 89 CHR patients, more than two-thirds met the criteria for Attenuated Positive Symptom Syndrome (APSS); and nearly a quarter met the criteria for Genetic Risk and Deterioration Syndrome (GRDS). The frequency of CHR syndromes peaked between the ages of 16 and 21years old and declined with subsequent age. The mean total and distress scores on the PQ-B in subjects with APSS and psychosis were significantly higher than in individuals with GDRS and patients without psychosis or CHR. High frequencies and strong correlations were found among some positive and non-specific symptoms in SIPS interviews. Among the 53 CHR participants who were followed-up for two years, 14 (26.4%) converted to psychosis. Of the non-converters, 53.8% were diagnosed with Axis I disorders. CONCLUSIONS: This two stage screening method can enhance detection of Chinese CHR patients in clinical settings. The validity of the procedures for detecting CHR is supported by rates of transition to psychosis and of non-converter Axis I disorders that are comparable to those reported in meta-analyses.