Pilot cohort study of obstructive sleep apnoea in community-dwelling people with schizophrenia.

OBJECTIVES: We aimed to assess the incidence of obstructive sleep apnoea (OSA) in people with schizophrenia, to explore clinical associates with OSA and how well OSA screening tools perform in this population. METHODS: All patients registered in a community outpatient Clozapine clinic, between January 2014 and March 2016, were consecutively approached to participate. Participants were screened for OSA using at home multichannel polysomnography (PSG) and were diagnosed with OSA if the apnoea-hypopnoea index (AHI) was >10 events/hr. Univariate comparison of participants to determine whether AHI > 10 events/hr was associated with demographic factors, anthropometric measures and psychiatric symptoms and cognition was performed. The sensitivity, specificity, positive predictive value and negative predictive value of the commonly used sleep symptoms scales and OSA screening tools were also determined. RESULTS: Thirty participants were recruited, 24 men and 6 women. Mean age was 38.8 (range: 25-60), and mean body mass index (BMI) was 35.7 (range 19.9-62.1). The proportion of participants with OSA (AHI > 10 events/hr) was 40%, 18 (60%) had no OSA, 4 (13%) had mild OSA (AHI 10.1-20), zero participants had moderate OSA (AHI 20.1-30) and 8 (27%) had severe OSA (AHI > 30). Diagnosis of OSA was significantly associated with increased weight, BMI, neck circumference and systolic blood pressure. Diagnosis of OSA was not significantly associated with Positive and Negative Symptoms Scale, Montgomery Asperger's Depression Rating Scale, Personal and Social Performance scale or Brief Assessment of Cognition for Schizophrenia scores. All OSA screening tools demonstrated poor sensitivity and specificity for a diagnosis of OSA. CONCLUSION: OSA was highly prevalent in this cohort of people with schizophrenia and was associated with traditional anthropometric OSA risk factors.

Short-term antidepressant treatment has long-lasting effects, and reverses stress-induced decreases in bone features in rats.

Antidepressants are among the most-prescribed class of drugs in the world and though weight gain is a common outcome of antidepressant treatment, that effect is not well understood. We employed an animal model comprised of 2 weeks of chronic restraint stress with antidepressant treatment, followed by diet-induced obesity. We showed that short-term antidepressant treatment had long-lasting effects, not only leading to weight gain, but also enhancing trabecular and cortical bone features in rats; therefore, weight gain in this model was different from that of the classic diet-induced obesity. Late in the post-restraint recovery period, antidepressant-treated animals were significantly heavier and had better bone features than saline-treated controls, when assessed in the distal femoral metaphysis. The propensity to gain weight might have influenced the rate of catch-up growth and bone allometry, as heavier animals treated with fluoxetine also had enhanced bone features when compared to non-stressed animals. Therefore, short-term antidepressant treatment ameliorated the long-term effects of stress on body growth and bone. Growth and bone structural features were associated with leptin levels, and the interaction between leptin levels and antidepressant was significant for bone mineral content, suggesting that short-term antidepressants in the context of long-term diet-induced obesity modified the role of leptin in bone formation. To our knowledge this is the first study reporting that short-term antidepressant treatment has long-lasting effects in restoring the effects of chronic stress in body weight and bone formation. Our findings may be relevant to the understanding and treatment of osteoporosis, a condition of increasing prevalence due to the aging population.

Performance of an algorithm-based approach to the diagnosis and management of functional gastrointestinal disorders: A pilot trial.

BACKGROUND: Recent advances in the development of diagnostic criteria and effective management options for functional gastrointestinal disorders (FGIDs) have not yet been integrated into clinical practice. There is a clear need for the development and validation of a simple clinical pathway for the diagnosis and management of FGIDs which can be used in primary care. METHODS: In this controlled pilot study, we designed and evaluated a non-specialist-dependent, algorithm-based approach for the diagnosis and management of FGIDs (ADAM-FGID). Patients referred to 1 tertiary referral center with clinically suspected functional gastrointestinal disorders were allocated to waitlist control or algorithm group. The algorithm group was screened for organic disease, and those without clinical alarms received a written FGID diagnosis and management options. All participants were followed up for 1 year. KEY RESULTS: The ADAM-FGID was found to be feasible and acceptable to both patients and primary healthcare providers. The diagnostic component identified that 39% of referrals required more urgent gastroenterological review than original triage category, with organic disease subsequently diagnosed in 31% of these. The majority of patients (82%) diagnosed with a FGID did not receive a relevant alternative diagnosis during follow-up. Patient buy-in to the model was good, with all reading the diagnostic/management letter, 80% entering management, and 61% reporting symptom improvement at 6 weeks. Moreover, 68% of patients and all referring doctors found the approach to be at least moderately acceptable. Patients reported being reassured by the approach and found the management options useful. Primary healthcare providers acknowledged the potential of this approach to reduce waiting times for endoscopic procedures and to provide reassurance to both patients and themselves. CONCLUSIONS & INFERENCES: This pilot study provides preliminary evidence to support a clinical pathway for the diagnosis and management of FGIDs which does not depend upon specialist review. Further rigorous testing within primary care is needed to conclusively establish safety and efficacy. However, this approach is safer than current management and has potential to build capacity by reducing specialist burden and expediting effective care.

Oncological outcomes in an Australian cohort according to the new prostate cancer grading groupings.

BACKGROUND: A new 5-tiered grading grouping system has recently been endorsed for reporting of prostate cancer (PCa) grade to better reflect escalating risk of progression and cancer death. While several validations of the new grade groupings have been undertaken, most have involved centralised pathological review by specialist urological pathologists. METHODS: Participants included 4268 men with non-metastatic PCa diagnosed between 2006 and 2013 from the multi-institutional South Australia Prostate Cancer Clinical Outcomes Collaborative registry. PCa-specific survival and biochemical recurrence-free survival were compared across the five grade groups using multivariable competing risk regression. RESULTS: For the entire cohort, risk of PCa death increased with increasing grade groups (at biopsy) Adjusted subdistribution-hazard ratios [sHR] and 95% confidence intervals [95%CI] were: 2.2 (1.5-3.6); 2.5 (1.6-4.2); 4.1 (2.6-6.7) and 8.7 (4.5-14.0) for grade groups II (pattern 3 + 4), III (pattern 4 + 3), IV (total score 8) and V (total score 9-10) respectively, relative to grade group I (total score < =6). Clear gradients in risk of PCa death were observed for radical prostatectomy (RP), but were less clear for those who had radiotherapy (RT) with curative intent and those who were managed conservatively. Likewise, risk of biochemical recurrence increased across grade groups, with a strong and clear gradient for men undergoing RP [sHR (95%CI): 2.0 (1.4-2.8); 3.8 (2.9-5.9); 5.3 (3.5-8.0); 11.2 (6.5-19.2) for grade groups II, III, IV and V respectively, relative to grade group I], and a less clear gradient for men undergoing RT. CONCLUSION: In general, the new five-tiered grade groupings distinguished PCa survival and recurrence outcomes for men with PCa. The absence of a clear gradient for RT may be due to heterogeneity in this patient group.

Tools for predicting patient-reported outcomes in prostate cancer patients undergoing radical prostatectomy: a systematic review of prognostic accuracy and validity.

BACKGROUND: Radical prostatectomy is a common surgical procedure performed to treat prostate cancer. Patient-reported outcomes after surgery include urinary incontinence, erectile dysfunction, decreased quality of life and psychological effects. Predictive tools to assess the likelihood of an individual experiencing various patient-reported outcomes have been developed to aid decision-making when selecting treatment. METHODS: A systematic review was undertaken to identify all papers describing tools for the prediction of patient-reported outcome measures in men with prostate cancer treated with radical prostatectomy. To be eligible for inclusion, papers had to provide a summary measure of accuracy. PubMed and EMBASE were searched from July 2007. Title/abstract screening, and full-text review were undertaken by two reviewers, while data extraction and critical appraisal was performed by a single reviewer. RESULTS: The search strategy identified 3217 potential studies, of which 191 progressed to full-text review and 14 were included. From these studies, 27 tools in total were identified, of which 18 predicted urinary symptoms, six predicted erectile function and one predicted freedom from a group of three outcomes ('trifecta') (biochemical recurrence, incontinence and erectile dysfunction). On the basis of tool accuracy (>70%) and external validation, two tools predicting incontinence and two tools predicting erectile dysfunction are ready for implementation. CONCLUSIONS: A small number of tools for the prediction of patient-reported outcomes following radical prostatectomy have been developed. Four tools were found to have adequate accuracy and validation and are ready for implementation for the prediction of urinary incontinence and erectile dysfunction.

St. Gallen endocrine response classes predict recurrence rates over time.

BACKGROUND: In 2007 the St. Gallen consensus panel defined three endocrine response classes: highly endocrine responsive (ER-H), incomplete endocrine responsive (ER-I) and non-endocrine responsive tumours (ER-N). However, it is uncertain whether ER-I tumours are less responsive than ER-H tumours. We investigated whether recurrence rates vary over time between response classes. Additionally, we investigated the most predictive response class definition for tamoxifen benefit. PATIENTS AND METHODS: We recollected tumours from 646 patients who participated in a randomized trial of adjuvant tamoxifen vs. OBSERVATION: Estrogen receptor (ER), progesterone receptor (PgR), HER2 status and tumour grade were revised centrally. St. Gallen classes were evaluated for recurrence free interval (RFI). Change in hazards over time was assessed. Subsequently, 6 alternative response class definitions were compared to optimize the cut-off for PgR and ER. RESULTS: Schoenfeld residuals indicate a failure of proportional hazards between the endocrine response groups (p = 0.0001). The HR for recurrence risk shifted over time with the ER-H group initially being at lower risk (HR ER-H vs. ER-I 0.5), but after six years the recurrence risk increased (HR 1.9). The cut-off values for ER and PgR that statistically best discriminated RFI in the first 4 years for lymph node positive patients were ER ≥ 50% and PgR ≥ 75%. CONCLUSION: We demonstrated a marked variability in endocrine therapy benefit. Patients with ER-H tumours have a larger benefit during adjuvant tamoxifen and in the first years after accomplishing of the therapy, but suffer from late recurrences. This might have implications for optimal treatment duration.

Functional optical coherence tomography of pigmented lesions.

BACKGROUND: Cutaneous melanomas are diagnosed worldwide in 231,130 patients per year. The sensitivity and specificity of melanoma diagnosis expresses the need for an additional diagnostic method. Optical coherence tomography (OCT) has shown that it allows morphological (qualitative) description of image features and quantitative analysis of pathology related light scattering by means of the attenuation coefficient (µoct ). OBJECTIVE: We hypothesize that OCT images of nevi will differ qualitatively and quantitatively from melanomas. METHODS: Forty lesions from 33 consecutive patients were imaged with OCT. After data acquisition, excision was performed. Epidermal layer thickness was measured and values of µoct were extracted from 200 OCT images of pigmented lesions. RESULTS: Morphologically, absence of the lower border of the lesion was characteristic for melanoma (P = 0.02). Also, the µoct was different between benign and malignant lesions (P = 0.02). There were no differences in epidermal layer thickness of benign lesions and melanoma. CONCLUSION: Although this preliminary study comprised a small number of patients, quantitative analysis of OCT images in pigmented skin lesions give valuable additional information about lesions characteristics. When using the attenuation coefficient, it might be possible to distinguish between benign lesions and melanomas.

Surgical wound complications after groin dissection in melanoma patients - a historical cohort study and risk factor analysis.

BACKGROUND AND OBJECTIVES: Wound complications occur frequently after inguinal lymph node dissection (ILND) in melanoma patients. Evidence on risk factors for complications is scarce and inconsistent. This study assessed wound complication rates after ILND and investigated associated risk factors, in the melanoma unit of a specialised cancer hospital. METHODS: A chart review was conducted of all patients on whom inguinal lymph node dissection had been performed between 2003 and 2013. Wound infections, seroma formation and skin flap problems were assessed according to explicit definitions and graded through the modified Clavien system. Univariable and multivariable penalized logistic regression was used to identify risk factors. The primary factors of interest were body mass index, age, smoking, diabetes, cardiovascular and/or pulmonal comorbidity, palpable disease and postoperative bedrest. Additionally, the influence of incision-type, sartorius transposition, saphenous vein sparing and skin removal was examined. RESULTS: A total of 145 procedures was examined. One or more complications occurred in 104 (72%) of the procedures; wound infection in 45%, seroma formation in 37% and skin flap problems in 26%. The only statistically significant risk factor was age (odds ratio for one standard deviation increase: 1.46, 95%CI 1.01-2.14, p = 0.05). CONCLUSIONS: Wound complication rates after ILND in melanoma patients are high. Age was the only predictor of complications in this cohort, other previously identified risk factors could not be confirmed.

A predictive model combining human epididymal protein 4 and radiologic features for the diagnosis of ovarian cancer.

OBJECTIVE: Ovarian cancer is the leading cause of death in women with gynecologic cancer. CA125 is the commonly used biomarker in the diagnosis of ovarian cancer, but has limitations in both sensitivity and specificity. Human Epididymal secretory protein (HE4) is a promising biomarker and is included in the Risk of Ovarian Malignancy Algorithm (ROMA) score, which is suggested to further increase the diagnostic accuracy than either marker alone. However, information from ultrasound and CT-scan is not included in this algorithm. This study evaluated the diagnostic accuracy of HE4 in the pre-operative diagnosis of ovarian cancer and the predictive values of biomarkers, ultrasound and CT-scan and combinations hereof. METHODS: HE4 and CA125 were measured in 361 subjects (34 benign, 147 ovarian cancer and 180 controls). Sensitivity, specificity and area under the curve (AUC) for CA125, HE4, ROMA and RMI scores were calculated using the receiver operating characteristic (ROC) methodology. The additional predictive value of ultrasound or CT-scan to the individual markers was analyzed using logistic regression. RESULTS: The sensitivity in predicting ovarian cancer of CA125 was 91% and of HE4 90%. The specificity was 65% and 97% respectively. HE4 demonstrated the highest discrimination (ROC-AUC=0.96), compared to ROMA, RMI and CA125 (AUC=0.95, 0.89 and 0.90 respectively). ROMA did not improve when it was combined with different ultrasound factors. The presence of intra-abdominal metastasis on CT-scan improved the discriminative potential of HE4 (p=0.0004). CONCLUSION: HE4 in combination with CT-scan may be incorporated in the diagnostic work-up in women with a pelvic mass.

A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. PATIENTS AND METHODS: A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). RESULTS: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49-0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively. CONCLUSIONS: PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology. STUDY REGISTRATION NUMBER: NCT00835471.

CYP2C19 2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment.

Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I-III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1-3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19 2 and CYP2C19 17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19 17. Patients with at least one CYP2C19 2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19 2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19 2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19 2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment.

The effect of prophylactic calcium and magnesium infusions on the incidence of neurotoxicity and clinical outcome of oxaliplatin-based systemic treatment in advanced colorectal cancer patients.

BACKGROUND: Peripheral sensory neurotoxicity is a frequent and potentially debilitating side effect of oxaliplatin treatment. Calcium and magnesium (Ca/Mg) infusions are frequently used to prevent this toxicity. However, concerns about a negative impact of Ca/Mg infusions on outcome have been raised. We retrospectively assessed the effect of Ca/Mg infusions on the incidence of neurotoxicity and on clinical outcome in advanced colorectal cancer (ACC) patients treated in the phase III CAIRO2 study. MATERIALS AND METHODS: Seven hundred and fifty five previously untreated ACC patients were randomised between treatment with capecitabine, oxaliplatin and bevacizumab or the same combination with the addition of cetuximab. Patients were retrospectively divided into two groups: patients in the Ca/Mg(+) group received Ca/Mg at least during their first treatment cycle, and patients in the Ca/Mg(-) group did not. RESULTS: Seven hundred and thirty two patients were evaluable for this analysis. The Ca/Mg(+) group consisted of 551 patients, the Ca/Mg(-) group consisted of 181 patients. The incidence of all grade neurotoxicity in the Ca/Mg(+) group and the Ca/Mg(-) group was 85% and 92%, respectively (p = 0.02), and the incidence of grade ≥ 2 neurotoxicity was 40% and 45%, respectively (p = 0.22). The median PFS in the Ca/Mg(+) versus Ca/Mg(-) group was 10.1 versus 10.7 months (p = 0.92), the median OS was 19.8 versus 20.7 months (p = 0.10), and the response rate was 43.1% versus 50% (p = 0.11), respectively. CONCLUSIONS: In this largest retrospective analysis to date we observed that Ca/Mg infusions significantly reduced all grade oxaliplatin-related neurotoxicity. Ca/Mg infusions did not affect the clinical efficacy of treatment.