A Challenging Case of Tumor-Induced Osteomalacia: Pathophysiological and Clinical Implications.

We investigated the usefulness of fibroblast growth factor 23 (FGF23) intraoperative assay to monitor tumor resection in patients with oncogenic osteomalacia. A 33-year-old man with 5 years' history of lumbar and pelvis pain together with multiple vertebral fractures was admitted to our hospital. He was diagnosed with ankylosing spondylitis 1 year before. Laboratory investigation showed low tubular reabsorption of phosphate (0.41 mmol/L) despite chronic hypophosphatemia (0.39/L). Increased plasma values of FGF23 (673 pg/mL; n.v. < 95 pg/mL) were also observed. A full-body CT scan showed two suspicious areas in the head of the right femur and in the right tibia; however, the Octreoscan™ showed an increased uptake of the tracer only in the femur. We decided to remove first the head femur lesion and perform intraoperative FGF23 assay to confirm tumor resection; if this had been unsuccessful, we would have extended the operation to excise the second bone lesion. FGF23 basal values and 10, 60, and 225 min after excision of the femoral head were 423, 127, 56, and 30 pg/mL, respectively. The brisk fall of FGF23 values suggested that the head femur lesion was responsible for the syndrome. Histological examination revealed a mesenchymal highly vascular tumor. This is the first report showing the possibility of intraoperative FGF23 assay to monitor tumor resection in patients with tumor-induced osteomalacia.

Circulating tumor cells in high-risk nonmetastatic colorectal cancer.

The identification of patients at higher risk of recurrence after primary colorectal cancer resection is currently one of the challenges facing medical oncologists. Circulating tumor cell (CTC) may represent a surrogate marker of an early spread of disease in patients without overt metastases. Thirty-seven high-risk stages II-III colorectal cancer patients were evaluated for the presence of CTC. Enumeration of CTCs in 7.5 ml of blood was carried out with the FDA-cleared CellSearch system. CTC count was performed after primary tumor resection and before the start of adjuvant therapy. CTC was detected in 22 % of patients with a significant correlation with regional lymph nodes involvement and stage of disease. No significant correlation was found among the presence of CTC and other clinicopathological parameters. These data suggest that CTCs detection might help in the selection of high-risk stage II colorectal cancer patient candidates for adjuvant chemotherapy.

Rivastigmine patch ameliorates depression in mild AD: preliminary evidence from a 6-month open-label observational study.

Here we investigated the effect of the rivastigmine patch alone on depression in 50 mild Alzheimer's disease (AD) patients with comorbid major depressive episode (MDE). First diagnosis acetyl-cholinesterase inhibitor and psychoactive drug-free outpatients (n=50) were recruited in memory clinics and reassessed after 3 and 6 months. Global cognitive functioning, depressive symptoms and MDE frequency were evaluated with the Mini Mental State Examination, the CERAD Dysphoria scale and the modified DSM-IV criteria for MDE in AD. MDE frequency reduced significantly from the first diagnostic visit (100%) to the 6-month follow-up (62%). We also found a significant reduction in CERAD Dysphoria scores that decreased from 6.2±3.9 mean±standard deviation to 4.9±4.5 at the 6-month follow-up. In AD patients with MDE rivastigmine alone can have a positive impact on depressive phenomena. Thus, future controlled study are justified to definitively verify if rivastigmine alone may improve depression in AD.

Genetic aspects underlying the normocalcemic and hypercalcemic phenotypes of primary hyperparathyroidism.

PURPOSE: Hypercalcemic primary hyperparathyroidism (PHPT) is a common endocrine disorder that has been very well characterized. In contrast, many aspects of normocalcemic primary hyperparathyroidism (NPHPT) such as natural history, organ damage, and management are still matter of debate. In addition, both the pathophysiology and molecular basis of NPHPT are unclear. We investigated whether PHPT and NPHPT patient cohorts share the same pattern of genetic variation in genes known to be involved in calcium and/or bone metabolism. RESEARCH DESIGN AND METHODS: Genotyping for 9 single nucleotide polymorphisms (SNPs) was performed by Real-Time PCR (TaqMan assays) on 27 NPHPT and 31 PHPT patients evaluated in a tertiary referral Center. The data of both groups were compared with 54 in house-controls and 503 subjects from the 1000 Genomes Project. All groups were compared for allele/haplotype frequencies, on a single locus, two loci and multi-locus basis. RESULTS: The NPHPT group differed significantly at SNPs in OPG and ESR1. Also, the NPHPT cohort was peculiar for pairwise associations of genotypes and for the overrepresentation of unusual multilocus genotypes. CONCLUSIONS: Our NPHPT patient set harbored a definitely larger quota of genetic diversity than the other samples. Specific genotypes may help in defining subgroups of NPHPT patients which deserve ad hoc clinical and follow-up studies.

Alexithymia is a non-motor symptom of Parkinson disease.

OBJECTIVES: : To investigate whether alexithymia is linked to the disease process or to psychopathology, particularly depression, in Parkinson disease (PD) patients. DESIGN: : Cross-sectional study. SETTING: : Neuropsychiatry outpatient clinic. PARTICIPANTS: : One hundred PD patients and 100 comparison subjects (CS). MEASUREMENTS: : PD patients and CS underwent a clinical and neuropsychiatric evaluation. Alexithymia was assessed with the 20-item Toronto Alexithymia Scale (TAS-20). Severity of depressive symptoms was measured with the Beck Depression Inventory. A structured psychiatric interview was used to diagnose major and minor depression. Logistic regression analyses with 95% confidence intervals (CI) were used to assess the association between alexithymia and PD. RESULTS: : Alexithymia occurred twice as often in PD patients (22%) as in CS (11%) and major depressive disorder occurred twice as often in CS (30%) than in PD (16%). The frequency of minor depression was almost identical (about 40%) in the 2 groups. Alexithymia was also associated with PD independently from depression. Indeed, after adjustment for sociodemographic factors, antidepressant use and depression severity, PD patients had an almost fourfold higher risk of having alexithymia (OR: 3.9, 95% CI: 1.5-10.0) and 24 times increased odds of having high scores on the TAS-20 items assessing difficulty in identifying emotions than CS (OR: 23.7, 95% CI: 10.1-55.6). CONCLUSIONS: : Our findings suggest that alexithymia is a depression-independent phenomenon in PD patients and may be associated with the disease process. Alexithymia is an important nonmotor symptom of PD and should be considered in patient assessment and management.

Opioid-Induced Constipation in Real-World Practice: A Physician Survey, 1 Year Later.

INTRODUCTION: Opioid-induced constipation (OIC) is the most common adverse effect of opioid therapy, but it is underdiagnosed and undertreated. Last year, a survey among Italian healthcare providers revealed important differences in the clinical management of OIC across physician specialties, the need of standardization of diagnosis and treatment, and the urgency of further education. Herein, we submitted an updated version of the survey to the same cohort of experts to evaluate potential progress. METHODS: The online survey included 15 questions about OIC. Responses were analyzed descriptively and aggregated by physician specialty. RESULTS: A total of 190 physicians completed the survey. Most respondents (65%) did not feel adequately educated about OIC despite general consensus regarding interest in the topic and acknowledgement of OIC impact on patients' QoL and adherence to opioid therapy. Overall, 55-77% of physicians regularly evaluated intestinal function or OIC symptoms in patients receiving opioid therapy, with one-third of respondents implementing it in the past year. Even though the most common method for assessment was still patient diary, the use of specific scales underwent a small but significant increase compared to the previous year, with major implementation in the use of Rome IV criteria. As regards first-line treatment, most respondents (49%) preferred macrogol prophylaxis followed by macrogol plus another laxative. For second-line treatment, we revealed a growth in the prescription of peripherally acting mu-opioid receptor antagonists (PAMORAs), with 46% of all the respondents having increased their use during the past year. CONCLUSIONS: Despite some limitations, our study demonstrated a slow but important step closer to standardization of diagnosis and treatment of OIC. Further educational and training efforts should be put in place to favor best evidence-based clinical practice.

New Perspectives on the Adverse Effects of NSAIDs in Cancer Pain: An Italian Delphi Study from the Rational Use of Analgesics (RUA) Group.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs for cancer pain. We used the Delphi methodology to evaluate the opinions of clinicians on NSAIDs and paracetamol, with a specific focus on their safety profile. Consensus was reached on seven statements. A high level of consensus was reached regarding the use of NSAIDs and gastrointestinal, cardiovascular, and renal risk in patients taking low-dose aspirin and assessment of liver function during long-term treatment with paracetamol. Consensus was also reached that assessment and monitoring of eGFR are important in the elderly being administered NSAIDs. It was further agreed that NSAIDs can often play a key role in association with opioids in the treatment of cancer pain and that paracetamol is the analgesic of first choice for patients with mild chronic pain. When NSAIDs are administered in combination with steroids, it was agreed that the risk of gastrointestinal damage is increased since steroids delay the healing of ulcers and that paracetamol can be used during pregnancy and does not affect the health of the fetus. This Delphi study highlights that there is poor agreement on how these drugs are routinely prescribed. However, a consensus was reached for seven key statements and may represent a valid contribution to daily practice.

Impact and Consequences of Opioid-Induced Constipation: A Survey of Patients.

INTRODUCTION: Opioids are a valuable tool to help achieve control of pain. However, opioid-induced constipation (OIC) is an important limitation of treatment with this class of drugs. METHODS: To better understand the impact of OIC on patient-reported outcomes, we carried out a survey involving patients being treated with opioids. Both ad hoc questions and the PROMIS and PAC-SYM and PAC-QOL scores were used. RESULTS: Of the 597 participants, 150 (25%) had cancer-related pain, and 447 (75%) had non-cancer pain; 66% experienced OIC. PROMIS pain interference questions indicated that pain is more likely to interfere with a patient's life when they have OIC. PAC-QOL and PAC-SYM revealed that 58% of patients with non-cancer pain and OIC reported at least one "severe" or "very severe" constipation symptom, compared to 83% with cancer-related pain. Younger age and less time on opioids were associated with greater impact of OIC on quality of life. Only 41% of patients were satisfied with how their constipation was managed. Over 50% of those with non-cancer pain said that they modified their opioid regimen due to constipation, vs. 6% of those with cancer pain. Constipation had been discussed with the healthcare provider (HCP) in 48% of non-cancer patients and in 73% of cancer patients. In those with chronic pain and OIC, 24% expressed varying degrees of dissatisfaction with the healthcare system, vs. 37% in those with cancer pain and OIC. CONCLUSION: Our results provide additional evidence that management of OIC is inadequate in many cases. Moreover, they indicate that there is a definite need for better education about OIC among HCPs.

Common Clinical Practice for Opioid-Induced Constipation: A Physician Survey.

BACKGROUND: Opioid-induced constipation (OIC) remains an important clinical obstacle despite the availability of several guidelines and pharmacological options for its management. Here, we surveyed common practices and perceptions about OIC among physicians who prescribe opioids in Italy. METHODS: The online survey included 26 questions about OIC. Responses were analyzed descriptively and aggregated by physician specialty. RESULTS: A total of 501 physicians completed the survey. Most respondents (67%) did not feel adequately educated about OIC despite general consensus regarding interest in the topic. Overall, 62-75% of physicians regularly evaluated intestinal function or OIC symptoms in patients receiving opioid therapy. The most common method for assessment was patient diary; few physicians used a validated instrument such as the Rome IV criteria. Psychiatrists and addiction specialists showed the lowest interest and poorest practices. Most respondents (78%) preferred macrogol prophylaxis followed by macrogol plus another laxative for first-line treatment of OIC symptoms. Peripheral-acting mu opioid receptor antagonists (PAMORAs) were not widely used among physicians; 61% had never prescribed a PAMORA for OIC. CONCLUSION: Our findings reveal important differences in clinical practice for OIC across physician specialties. Additional formative efforts are necessary to improve awareness about best practices in OIC.

Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors.

The prognostic value associated with the detection of circulating tumor cells (CTCs) in metastatic breast cancer by the CellSearch technology raise additional issues regarding the biological value of this information. We postulated that a drug-resistance profile of CTCs may predict response to chemotherapy in cancer patients and therefore could be used for patient selection. One hundred 5 patients with diagnosis of carcinoma were enrolled in a prospective trial. CTCs were isolated from peripheral blood, and positive samples were evaluated for the expression of a panel of genes involved in anticancer drugs resistance. The drug-resistance profile was correlated with disease-free survival (DFS; patients in adjuvant setting) and time to progression (TTP; metastatic patients) in a 24-months follow-up. Objective response correlation was a secondary end point. Fifty-one percent of patients were found positive for CTCs while all blood samples from healthy donors were negative. The drug-resistance profile correlates with DFS and TTP (p < 0.001 in both). Sensitivity of the test: able to predict treatment response in 98% of patients. Specificity of the test: 100%; no sample from healthy subject was positive for the presence of CTCs. Positive and negative predictive values were found to be 96.5 and 100%, respectively. We identified a drug-resistance profile of CTCs, which is predictive of response to chemotherapy, independent of tumor type and stage of disease. This approach may represent a first step toward the individualization of chemotherapy in cancer patients.

Management of anaemia in prostate cancer.

Anaemia is a frequent complication of prostate cancer and of its treatments. In Europe prostate cancer accounts for the 10.8% of all malignant neoplasms. Iatrogenic hypogonadism and age-related physiologic changes along with nutritional deficits contribute to increase prevalence of prostate cancer related anaemia. The reason of the present review is to provide clinicians with all aspects of a frequent and multifactorial co-morbidity, whose effects are often underestimated. Erythropoiesis pathology and causes of anaemia in prostate cancer are reviewed. Critical issues of clinical management of anaemia in prostate cancer are discussed.

Prognostic significance of survivin-expressing circulating tumour cells in T1G3 bladder cancer.

OBJECTIVE: To evaluate the prognostic significance of survivin in tumour tissues and that of survivin-expressing circulating tumour cells (CTCs) in T1G3 bladder tumours, as the prognosis of T1G3 bladder cancer is highly variable and unpredictable from clinical and pathological prognostic factors. PATIENTS AND METHODS: The study included 54 patients with T1G3 non-muscle-invasive bladder cancer. Additional inclusion criteria were: tumour size <3 cm, absence of carcinoma in situ and multifocality. The planned follow-up was 24 months. Survivin was evaluated by reverse transcription-polymerase chain reaction in tumour tissues. CTCs were isolated from blood by CELLection Dynabeads (Invitrogen, Carlsbad, CA, USA) coated with the monoclonal antibody towards the human epithelial cell adhesion molecule. Cells were lysed and Dynabeads Oligo(dT) was used to capture poly A + mRNA. cDNA was synthesized and analysed for the expression of CD45, CK8 and survivin. The primary endpoint was disease-free survival (DFS); the favourable group at 24 months was defined as that with no clinical evidence of disease; the unfavourable group was that with evidence of recurrent disease or progressive disease. Tumour survivin expression and presence of CTC were correlated with DFS. Multivariate analysis was used to investigate whether the presence of CTC was an independent indicator of DFS. RESULTS: Survivin was found in half of the tumours; patients with survivin-negative tumours had a longer DFS than those with survivin-positive tumours (chi-square, P = 0.029). CTCs were found in 24/54 patients (44%); 92% of CTC expressed survivin. The difference in DFS between CTC-ve and CTC+ve patients was statistically significant (chi-square, P < 0.001). The presence of CTC was an independent prognostic factor for DFS (P < 0.001). CONCLUSION: The presence of CTC is an independent prognostic factor in patients with T1G3 bladder cancer.

Occurrence of neuropsychiatric symptoms and psychiatric disorders in mild Alzheimer's disease and mild cognitive impairment subtypes.

BACKGROUND: Neuropsychiatric disorders are common in cognitively impaired older persons, and associated with institutionalization and caregiver stress in Alzheimer's disease (AD). Few studies have compared the occurrence of both psychiatric disorders and neuropsychiatric symptoms in patients with AD and mild cognitive impairment (MCI) subtypes. We aimed to investigate the frequency of psychiatric disorders and neuropsychiatric symptoms in AD and MCI patients, compared to controls. METHODS: We included 245 outpatients of a memory clinic in Rome, Italy (119 AD; 68 multidomain-MCI; 58 amnestic-MCI) and 107 controls. Categorical disorders of depression and apathy were diagnosed with structured interviews. Symptoms were evaluated with the Neuropsychiatric Inventory (NPI). The odds ratios (OR) of patients having neuropsychiatric symptoms compared to controls were calculated with logistic regression, adjusted for sociodemographic and clinical variables. RESULTS: A large proportion of AD (49.6%) and multidomain-MCI (44.1%) patients had depression disorder. Apathy disorder was common in AD (51.3%) but less frequent in amnestic-MCI (6.9%) and multidomain-MCI (14.7%). AD patients were three times more likely to have depression disorders (OR = 3.0, CI = 1.1-7.6) or apathy (OR = 16.9, CI = 4.6-61.8) compared to amnestic-MCI, and seven times more likely to have apathy disorder than multidomain-MCI (OR = 7.5, CI = 3.0-19.2). After apathy and depression, the most prevalent neuropsychiatric symptoms in AD and MCI were anxiety, agitation, irritability, night-time behaviors, and appetite disturbances. There was an increasing prevalence of many neuropsychiatric symptoms with increasing severity of cognitive syndromes. CONCLUSIONS: Clinicians should consider the relevance of neuropsychiatric disorders and symptoms in patients with cognitive disturbances, and incorporate a thorough psychiatric examination in the evaluation of patients.

What to Do and What Not to Do in the Management of Opioid-Induced Constipation: A Choosing Wisely Report.

INTRODUCTION: Despite the essential utility of opioids for the clinical management of pain, opioid-induced constipation (OIC) remains an important obstacle in clinical practice. In patients, OIC hinders treatment compliance and has negative effects on quality of life. From a clinician perspective, the diagnosis and management of OIC are hampered by the absence of a clear, universal diagnostic definition across disciplines and a lack of standardization in OIC treatment and assessment. METHODS: A multidisciplinary panel of physician experts who treat OIC was assembled to identify a list of ten corrective actions-five "things to do" and five "things not to do"-for the diagnosis and management of OIC, utilizing the Choosing Wisely methodology. RESULTS: The final list of corrective actions to improve the diagnosis and clinical management of OIC emphasized a need for: (i) better physician and patient education regarding OIC; (ii) systematic use of diagnostically validated approaches to OIC diagnosis and assessment (i.e., Rome IV criteria and Bristol Stool Scale, respectively) across various medical contexts; and (iii) awareness about appropriate, evidence-based treatments for OIC including available peripheral mu-opioid receptor antagonists (PAMORAs). CONCLUSIONS: Physicians who prescribe long-term opioids should be forthcoming with patients about the possibility of OIC and be adequately versed in the most recent guideline recommendations for its management.

Correction to: What to Do and What Not to Do in the Management of Opioid-Induced Constipation: A Choosing Wisely Report.

The original article can be found online.

Subclinical Cognitive and Neuropsychiatric Correlates and Hippocampal Volume Features of Brain White Matter Hyperintensity in Healthy People.

White matter hyperintensities (WMH) are associated with brain aging and behavioral symptoms as a possible consequence of disrupted white matter pathways. In this study, we investigated, in a cohort of asymptomatic subjects aged 50 to 80, the relationship between WMH, hippocampal atrophy, and subtle, preclinical cognitive and neuropsychiatric phenomenology. Thirty healthy subjects with WMH (WMH+) and thirty individuals without (WMH-) underwent comprehensive neuropsychological and neuropsychiatric evaluations and 3 Tesla Magnetic Resonance Imaging scan. The presence, degree of severity, and distribution of WMH were evaluated with a semi-automated algorithm. Volumetric analysis of hippocampal structure was performed through voxel-based morphometry. A multivariable logistic regression analysis indicated that phenomenology of subclinical apathy and anxiety was associated with the presence of WMH. ROI-based analyses showed a volume reduction in the right hippocampus of WMH+. In healthy individuals, WMH are associated with significant preclinical neuropsychiatric phenomenology, as well as hippocampal atrophy, which are considered as risk factors to develop cognitive impairment and dementia.

Depression and cancer: an unexplored and unresolved emergent issue in elderly patients.

Despite the high prevalence of depressive disorders in cancer patients and elderly people, the topic of depression in elderly cancer patients still remains unexplored. This emerges from a systematic review of the literature conducted to investigate issues of depression, diagnosis, pathogenesis, treatment and their complex neuroimmunobiological interactions. Indeed, it becomes apparent that depression in elderly patients with cancer may have a peculiar phenomenology. In addition, the moderate rate of major depressive disorder and the high rate of minor depressive disorder are accompanied by subthreshold forms of depression that are at risk to be underrecognized and untreated. Immune dysfunction may represent a common pathogenic ground of depression, cancer and aging. This may have important implications for treatment. In the near future, we need to develop validated mood disorder diagnoses and verify antidepressant treatment efficacy for elderly cancer patients with depression in order to improve their clinical outcome and quality of life.

Interleukin-18 produced by peripheral blood cells is increased in Alzheimer's disease and correlates with cognitive impairment.

A body of evidence indicates that inflammation plays a pivotal role in AD pathogenesis. IL-18 is a pro-inflammatory cytokine produced in the brain, emerging to be implicated in AD. Although no differences in circulating IL-18 levels were measured between AD patients and controls, a significant increased production of IL-18 was obtained from stimulated blood mononuclear cells of AD patients. This was true particularly in AD subjects carrying the C/C genotype at the -607 position of IL-18 gene promoter. Furthermore, a significant correlation between IL-18 production and cognitive decline was observed in AD patients. Overall, these data indicate that IL-18-related inflammatory pathways, probably also in virtue of polymorphic IL-18 gene influence, are exacerbated in AD patients, and that this cytokine may indeed participate in pathogenic processes leading to dementia.

Facial emotion recognition deficit in amnestic mild cognitive impairment and Alzheimer disease.

OBJECTIVES: A deficit in facial emotion recognition was described in patients with Alzheimer disease (AD). However, this issue has been underexplored in subjects with amnestic mild cognitive impairment (a-MCI). Thus, the authors aimed to determine whether a deficit in facial emotion recognition is present in a-MCI phase and whether this is intensity dependent. A secondary aim was to investigate relationships between facial emotion recognition and cognitive performances. DESIGN: Case-control study. SETTING: Memory clinic. PARTICIPANTS: Fifty a-MCI patients, 50 mild AD patients, and 50 comparison subjects (COM) were enrolled. MEASUREMENTS: Information about facial emotion recognition was obtained from Penn Emotion Recognition Test. The Mental Deterioration Battery was used to measure cognitive impairment. RESULTS: Mild AD patients were more impaired in the recognition of almost all emotional stimuli of all intensities than a-MCI and COM subjects. However, there was an increased progression only in low-intensity facial emotion recognition deficit from COM to a-MCI to mild AD patients. In particular, a-MCI subjects differed significantly from COM in low-intensity fearful face recognition performance. This deficit in a-MCI patients was explained by the short-term verbal memory impairment, whereas the same deficit in mild AD patients was explained by the long-term verbal memory impairment. CONCLUSIONS: Emotion recognition progresses from a deficit in low-intensity fearful facial recognition in a-MCI phase to a deficit in all intensities and emotions in mild AD. This could be an effect of the progressive degeneration of brain structures modulating emotional processing. An early detection of emotional impairment in MCI phases of dementia may have clinical implications.