Blazar spectral variability as explained by a twisted inhomogeneous jet.

Blazars are active galactic nuclei, which are powerful sources of radiation whose central engine is located in the core of the host galaxy. Blazar emission is dominated by non-thermal radiation from a jet that moves relativistically towards us, and therefore undergoes Doppler beaming. This beaming causes flux enhancement and contraction of the variability timescales, so that most blazars appear as luminous sources characterized by noticeable and fast changes in brightness at all frequencies. The mechanism that produces this unpredictable variability is under debate, but proposed mechanisms include injection, acceleration and cooling of particles, with possible intervention of shock waves or turbulence. Changes in the viewing angle of the observed emitting knots or jet regions have also been suggested as an explanation of flaring events and can also explain specific properties of blazar emission, such as intra-day variability, quasi-periodicity and the delay of radio flux variations relative to optical changes. Such a geometric interpretation, however, is not universally accepted because alternative explanations based on changes in physical conditions-such as the size and speed of the emitting zone, the magnetic field, the number of emitting particles and their energy distribution-can explain snapshots of the spectral behaviour of blazars in many cases. Here we report the results of optical-to-radio-wavelength monitoring of the blazar CTA 102 and show that the observed long-term trends of the flux and spectral variability are best explained by an inhomogeneous, curved jet that undergoes changes in orientation over time. We propose that magnetohydrodynamic instabilities or rotation of the twisted jet cause different jet regions to change their orientation and hence their relative Doppler factors. In particular, the extreme optical outburst of 2016-2017 (brightness increase of six magnitudes) occurred when the corresponding emitting region had a small viewing angle. The agreement between observations and theoretical predictions can be seen as further validation of the relativistic beaming theory.

Changes in PgR and Ki-67 in residual tumour and outcome of breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Limited data are available on the prognostic value of changes in the biological features of residual tumours following neoadjuvant therapies in breast cancer patients. PATIENTS AND METHODS: We collected information through the institutional clinical database on all consecutive breast cancer patients treated with neoadjuvant chemotherapy at the European Institute of Oncology (IEO), Milan, Italy, between 1999 and 2011. We selected patients who did not achieve pathological complete response at final surgery. All patients had a pathological evaluation, including ER, PgR, HER2 protein and Ki-67 expression carried out at the IEO both at diagnostic core biopsy and at final surgery. RESULTS: We identified a total of 904 patients. The 5% of patients who were ER positive at diagnostic biopsy had ER-negative residual tumour at final surgery. For PgR expression, 67% of the patients, whose tumours had a PgR >20% at diagnostic biopsy had a PgR <20% at final surgery. The Ki-67 expression changed from >20% to <20% in 40% of the patients. At the multivariate analysis, the decrease of PgR-immunoreactive cells correlated with improved outcome in terms of disease-free survival (DFS) [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.54-1.00, P 0.046]. In addition, the decrease of Ki-67 expression to <20% of the cells at final surgery was found to be associated with better outcome both in terms of DFS (HR 0.52; 95% CI 0.40-0.68 P < 0.0001) and overall survival (HR 0.45; 95% CI 0.32-0.64, P < 0.0001). CONCLUSION: The decrease of PgR and Ki-67 expression after preoperative chemotherapy has a prognostic role in breast cancer patients with residual disease.

Comparison of Onclarity Human Papillomavirus (HPV) Assay with Hybrid Capture II HPV DNA Assay for Detection of Cervical Intraepithelial Neoplasia Grade 2 and 3 Lesions.

Analytical and clinical performance validation is essential before introduction of a new human papillomavirus (HPV) assay into clinical practice. This study compares the new BD Onclarity HPV assay, which detects E6/E7 DNA from 14 high-risk HPV types, to the Hybrid Capture II (HC2) HPV DNA test, to concurrent cytology and histology results, in order to evaluate its performance in detecting high-grade cervical lesions. A population of 567 women, including 325 with ≥ASCUS (where ASCUS stands for atypical cells of undetermined significance) and any HC2 result and 242 with both negative cytology and negative HC2 results, were prospectively enrolled for the study. The overall agreement between Onclarity and HC2 was 94.6% (95% confidence intervals [CI], 92.3% to 96.2%). In this population with a high prevalence of disease, the relative sensitivities (versus adjudicated cervical intraepithelial neoplasia grades 2 and 3 [CIN2+] histology endpoints) of the Onclarity and HC2 tests were 95.2% (95% CI, 90.7% to 97.5%) and 96.9% (95% CI, 92.9% to 98.7%), respectively, and the relative specificities were 50.3% (95% CI, 43.2% to 57.4%) for BD and 40.8% (95% CI, 33.9%, 48.1%) for HC2. These results indicate that the BD Onclarity HPV assay has sensitivity comparable to that of the HC2 assay, with a trend to an increased specificity. Moreover, as Onclarity gives the chance to discriminate between the different genotypes, we calculated the genotype prevalence and the absolute risk of CIN2+: HPV 16 was the most prevalent genotype (19.8%) with an absolute risk of CIN2+ of 77.1%.

Framing deductive reasoning with emotional content: an fMRI study.

In the literature concerning the study of emotional effect on cognition, several researches highlight the mechanisms of reasoning ability and the influence of emotions on this ability. However, up to now, no neuroimaging study was specifically devised to directly compare the influence on reasoning performance of visual task-unrelated with semantic task-related emotional information. In the present functional fMRI study, we devised a novel paradigm in which emotionally negative vs. neutral visual stimuli (context) were used as primes, followed by syllogisms composed of propositions with emotionally negative vs. neutral contents respectively. Participants, in the MR scanner, were asked to assess the logical validity of the syllogisms. We have therefore manipulated the emotional state and arousal induced by the visual prime as well as the emotional interference exerted by the syllogism content. fMRI data indicated a medial prefrontal cortex deactivation and lateral/dorsolateral prefrontal cortex activation in conditions with negative context. Furthermore, a lateral/dorsolateral prefrontal cortex modulation caused by syllogism content was observed. Finally, behavioral data confirmed the influence of emotional task-related stimuli on reasoning ability, since the performance was worse in conditions with syllogisms involving negative emotions. Therefore, on the basis of these data, we conclude that emotional states can impair the performance in reasoning tasks by means of the delayed general reactivity, whereas the emotional content of the target may require a larger amount of top-down resources to be processed.

The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma.

BACKGROUND: Recent preclinical studies identified Axl, a tyrosine kinase receptor implicated in tumour progression and epithelial-to-mesenchymal transition, as a putative therapeutic target in malignant pleural mesothelioma (MPM), an invariably fatal malignancy with limited treatment options. Here, we studied the expression of Axl and its ligand Gas-6 (growth arrest signal-6) in primary specimens of MPM, correlating their expression levels with tumour phenotype and clinical outcomes. METHODS: Two independent cohorts of consecutive patients diagnosed with MPM were studied: a derivation cohort composed of 63 cases and a validation set of 35 cases. Clinical variables including patients' demographics, tumour stage, histotype, performance status (PS), Axl and Gas-6 staining were tested for predicting overall survival (OS) using univariate and multivariate analyses. RESULTS: In the derivation cohort, Axl (P=0.001) but not Gas-6 overexpression (P=0.35) emerged as a univariate prognostic factor for OS, together with stage (P=0.05), PS (P<0.001) hypoalbuminaemia (P<0.001) and anaemia (P<0.001). Multivariate analyses confirmed Axl overexpression (P=0.01), PS (P=0.01), hypoalbuminaemia (P<0.001) and anaemia (P=0.04) as independent predictors of OS. The prognostic role of Axl overexpression was externally validated in an independent cohort (P=0.03). CONCLUSION: Overexpression of Axl is found in the majority of MPM specimens and influences patient's survival independently from other established prognostic factors. Such information may support patient selection for future trials.

Prognostic role of CA15.3 in 7942 patients with operable breast cancer.

To assess the prognostic value of presurgical CA15.3 in a large cohort of patients with early breast cancer. A total of 7.942 consecutive patients with breast cancer operated at the European Institute of Oncology between 1998 and 2005 and with presurgical values of CA 15.3 available were included. We explored patterns of recurrence by baseline CA 15.3 values. Mean CA15.3 was 17.0 U/ml. CA15.3 was associated with age, tumor size, nodal involvement, Ki-67 labeling index, grade, HER2 expression, molecular subtype, and perivascular invasion. CA15.3 was independently associated with distant metastases [HR > 20 U/ml vs. ≤ 20 U/ml: 1.34 (95% CI 1.15-1.56)] and death [HR > 20 U/ml vs. ≤ 20 U/ml: 1.30 (95% CI 1.11-1.53)]. When considering CA15.3 as continuous variable, we observed a constant risk of metastasis and death from the lowest values to about 15-20 U/ml, and then a significantly increasing risk with increasing values of CA15.3. Finally, CA15.3 provided significant additional information to the common prognostic factors to predict the occurrence of metastases (C-index P value 0.04). In patients with operable breast cancer, presurgical CA15.3 value is an independent prognostic factor for metastases and deaths. CA15.3 provides additional information to the common prognostic factors and should be considered in the adjuvant therapeutic algorithm.

Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women.

BACKGROUND: To test the efficacy of levonorgestrel-release intrauterine device (LNG-IUD) plus gonadotropin-releasing hormone (GnRH) for treating women aged <40 years with atypical endometrial hyperplasia (AEH) or presumed International Federation of Gynecology and Obstetrics stage IA limited to the endometrium, well differentiated (G1), endometrioid endometrial cancer (EC), who wish to preserve their fertility. PATIENTS AND METHODS: A prospective observational study was conducted. Treatment consisted on the insertion of an LNG-IUD for 1 year plus GnRH analogue for 6 months. RESULTS: From January 1996 to June 2009, 20 and 14 patients with AEH and EC, respectively, were studied. Complete response rate was 95% in patients with AEH and 57.1% in women with EC-G1. A progression of the disease was observed in one (5%) and in four patients (28%) with AEH and EC, respectively. Four of 20 patients with AEH and 2 of 14 with EC-G1 experienced recurrences. The average relapse time was 36 months (range: 16-62 months). All of them were alive without evidence of disease at the last follow-up, mean: 29 months (range: 4-102 months). Nine women achieved 11 spontaneous pregnancies. CONCLUSIONS: The combined treatment showed effectiveness in a substantial proportion of patients with AEH and EC. Close follow-up during and after treatment is crucial.

XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study.

Malignant pleural mesothelioma (MPM) is a rare aggressive tumor associated with asbestos exposure. The possible role of genetic factors has also been suggested and MPM has been associated with single nucleotide polymorphisms (SNPs) of xenobiotic and oxidative metabolism enzymes. We have identified an association of the DNA repair gene XRCC1 with MPM in the population of Casale Monferrato, a town exposed to high asbestos pollution. To extend this observation we examined 35 SNPs in 15 genes that could be involved in MPM carcinogenicity in 220 MPM patients and 296 controls from two case-control studies conducted in Casale (151 patients, 252 controls) and Turin (69 patients, 44 controls), respectively. Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Two DNA repair genes were associated with MPM, i.e. XRCC1 and ERCC1. Considering asbestos-exposed only, the risk increased with the increasing number of XRCC1-399Q alleles (Casale: OR=1.44, 95%CI 1.02-2.03; Casale+Turin: OR=1.34, 95%CI 0.98-1.84) or XRCC1 -77T alleles (Casale+Turin: OR=1.33, 95%CI 0.97-1.81). The XRCC1-TGGGGGAACAGA haplotype was significantly associated with MPM (Casale: OR=1.76, 95%CI 1.04-2.96). Patients heterozygotes for ERCC1 N118N showed an increased OR in all subjects (OR=1.66, 95%CI 1.06-2.60) and in asbestos-exposed only (OR=1.59, 95%CI 1.01-2.50). When the dominant model was considered (i.e. ERCC1 heterozygotes CT plus homozygotes CC versus homozygotes TT) the risk was statistically significant both in all subjects (OR=1.61, 95%CI 1.06-2.47) and in asbestos-exposed only (OR=1.56, 95%CI 1.02-2.40). The combination of ERCC1 N118N and XRCC1 R399Q was statistically significant (Casale: OR=2.02, 95%CI 1.01-4.05; Casale+Turin: OR=2.39, 95%CI 1.29-4.43). The association of MPM with DNA repair genes support the hypothesis that an increased susceptibility to DNA damage may favour asbestos carcinogenicity.

Role of diffusion-weighted imaging in the differential diagnosis of benign and malignant lesions of the chest-mediastinum.

PURPOSE: We retrospectively evaluated the role of diffusion-weighted imaging (DWI) with fat and background signal suppression in the differential diagnosis of benign and malignant lesions of the chest-mediastinum by calculating the mean apparent diffusion coefficient (ADC) values. MATERIALS AND METHODS: Thirty-four patients with lung nodules/mediastinal masses underwent magnetic resonance (MR) imaging of the chest with conventional and DWI sequences. All patients had been previously studied with computed tomography (CT). After magnetic resonance (MR) imaging the patients underwent transthoracic CT-guided biopsy or mediastinoscopy. After the histopathological diagnosis had been obtained, the lesions were retrospectively divided into five groups: adenocarcinomas (n=16), squamous cell carcinomas (n=12), chronic pneumonias (n=2), malignant mediastinal tumours (n=2) and typical carcinoids (n=2). We compared ADC values in the different lesion groups using the Mann-Whitney U test. RESULTS: There were statistically significant differences (p<0.05) between ADC values of benign and malignant lesions. Using an ADC value of 1.25×10⁻³ mm²/s as a threshold, we were able to differentiate malignant from benign lesions with 91% diagnostic accuracy, 90% sensitivity, 100% specificity, 100% positive predictive value and 57% negative predictive value. CONCLUSIONS: Short-tau inversion-recovery echo-planar imaging (STIR-EPI) sequences applied to the chest-mediastinum provided potentially useful images for the differential diagnosis of benign and malignant lesions.

Compact radio emission indicates a structured jet was produced by a binary neutron star merger.

The binary neutron star merger event GW170817 was detected through both electromagnetic radiation and gravitational waves. Its afterglow emission may have been produced by either a narrow relativistic jet or an isotropic outflow. High-spatial-resolution measurements of the source size and displacement can discriminate between these scenarios. We present very-long-baseline interferometry observations, performed 207.4 days after the merger by using a global network of 32 radio telescopes. The apparent source size is constrained to be smaller than 2.5 milli-arc seconds at the 90% confidence level. This excludes the isotropic outflow scenario, which would have produced a larger apparent size, indicating that GW170817 produced a structured relativistic jet. Our rate calculations show that at least 10% of neutron star mergers produce such a jet.

Surgical pleurodesis for Vanderschueren's stage III primary spontaneous pneumothorax.

The aim of the present study was to determine the impact of various pleurodesis procedures on post-operative morbidity and late recurrence rate after surgical treatment of Vanderschueren's stage III primary spontaneous pneumothorax. Between January 2001 and June 2004, 208 consecutive patients (169 male and 39 female; mean (range) age 25 (12-39) yrs) were submitted to 220 video-assisted thoracoscopic surgical procedures for primary spontaneous pneumothorax. All patients underwent apical lung resection; 112 were assigned at random to mechanical pleural abrasion (group A) and 108 to apical pleurectomy (group B). The two groups of patients showed similar characteristics. No intra- or post-operative deaths occurred. Post-operative morbidity was 6.25% for group A and 12.9% for group B; the two groups exhibited a similar persistent post-operative air leak rate (5.3% in group A and 5.5% in group B), whereas haemothorax was significantly more frequent after apical pleurectomy (eight (7.4%) cases) than after pleural abrasion (one (0.9%) case). The mean duration of follow-up was 46 (24-66) months. Late recurrence occurred in five cases (4.6%) after apical pleurectomy, and in seven (6.2%) after mechanical pleural abrasion. Mechanical pleural abrasion by video-assisted thoracoscopic surgery is safer than apical pleurectomy in the treatment of primary spontaneous pneumothorax. No differences in late recurrence rate were observed between the two procedures.

Prognostic role of the extent of peritumoral vascular invasion in operable breast cancer.

BACKGROUND: The clinical relevance of the degree of peritumoral vascular invasion (PVI) in patients with no or limited involvement of the axillary nodes is unknown. MATERIALS AND METHODS: 2606 consecutive patients with pT1-3, pN0 (1586)-1a (1020) and M0, operated and counseled for medical therapy from 1/2000 to 12/2002, were prospectively classified according to the degree of PVI: absent (2017, 77.4%), focal (368, 14.1%), moderate (51, 2.0%) and extensive (170, 6.5%). RESULTS: Patients with extensive PVI were more likely to be younger, to have larger tumors, high tumor grade, axillary-positive nodes, high Ki-67 expression and HER2/neu over-expression compared with patients having less PVI (P for trend, <0.0001). In patients with node-negative disease a statistically significant difference in disease-free survival (DFS), risk of distant metastases and overall survival (OS) was observed at the multivariate analysis for extensive PVI versus no PVI (hazard ratios: 2.11, 95% CI, 1.02 to 4.34, P = 0.04 for DFS; 4.51, 95% CI, 1.96 to 10.4, P< 0.001 for distant metastases; 3.55, 95% CI, 1.24 to 10.1, P = 0.02 for OS). CONCLUSIONS: The extent of vascular invasion should be considered in the therapeutic algorithm in order to properly select targeted adjuvant treatment.

The role of surgery in the management of solitary pulmonary nodule in breast cancer patients.

AIMS: To assess the role of surgery in the diagnosis and treatment of a solitary pulmonary nodule (SPN) in patients who had received previous surgery for breast cancer. METHODS: A series of 79 consecutive patients who underwent surgery for an SPN between 1990 and 2003 after a curative resection for breast cancer were reviewed. RESULTS: Surgical diagnosis was obtained by open procedure before 1996 (37 cases), and by video-assisted thoracoscopic surgery (VATS) after 1996 (33 out of 42 cases, 9 open procedures) and intraoperative evaluation. Histology of SPN was primary lung cancer in 38 patients, pulmonary metastasis of breast cancer in 27, and benign condition in 14. VATS was converted to open procedure for anatomical resection in primary lung cancer and for the palpation of the lung in metastatic disease. Average disease-free interval from the initial mastectomy was significantly longer in primary lung cancer than in metastatic patients (179+/-107 vs 51+/-27 moths). Manual palpation identified multiple pulmonary nodules in 3 out of 27 metastatic patients. Five-year survival rate after pulmonary metastasectomy was 38% and was significantly influenced by disease-free interval; 5-year survival rate after resection of primary lung cancer was 43% and was significantly influenced by the pathological stage. CONCLUSIONS: VATS is a good procedure for diagnostic management of peripheral SPN. As SPN in breast cancer patients is primary lung cancer in half cases, it deserves confirmation of pathological diagnosis and appropriate surgical treatment. When breast cancer metastasis is demonstrated, open procedure must be performed to palpate the entire lung to exclude previously unknown nodules.

CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.

BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

Subarachnoid-pleural fistula due to blunt chest trauma. A case report.

Subarachnoid pleural fistula (SPF) due to blunt chest trauma is rare. When SPF isn't associated with any neurological deficits, its clinical diagnosis is possible only with high degree of suspicion. Presentation symptoms include dyspnea and respiratory distress caused by the collection of cerebral-spinal fluid in the pleural cavity. Computed tomography scan after myelography is helpful in confirming the site of the fistula. Possible dangerous complications are infections or pneumoencephalus. Some cases resolved spontaneously after bed rest or pleural drainage alone, while others required surgical repair. We report a case of spontaneous closure after pleural drainage and a brief period of mechanical ventilation.

Schwannoma of thyroid bed. A case report and considerations on interdisciplinary collaboration.

Schwannoma of the thyroid bed is extremely rare, but is known to simulate a thyroid nodule. A retrospective review is reported of a 64-year-old female patient with a thyroid nodule who had been submitted to pre-operative fine-needle aspiration biopsy, judged inadequate, following which total thyroidectomy was performed. On histological examination, the nodule (in the thyroid bed) was found to be a schwannoma. This case report stresses the importance of interdisciplinary collaboration. Better co-operation between surgeon, pathologist and radiologist may have led to correct pre-operative diagnosis with sparing of at least half the thyroid.

Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide.

In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients who gave informed consent to increase their pain for 30 min received a substance known to be non-hyperalgesic (saline solution) and were told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety, we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety.

Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain.

The treatment of neuropathic pain with opioid analgesics is a matter of controversy among clinicians and clinician scientists. Although neuropathic pain is usually believed to be only slightly responsive to opioids, several studies show that satisfactory analgesia can be obtained if adequate doses are administered. In the present study, we tested the effectiveness of buprenorphine in 21 patients soon after thoracic surgery (nociceptive postoperative pain) and 1 month after surgery in the same 21 patients who developed postthoracotomy neuropathic pain with a burning, electrical and shooting quality. According to a double-blind randomized study, the analgesic dose (AD) of buprenorphine needed to reduce the long-term neuropathic pain by 50% (AD50) was calculated and compared to the AD50 in the immediate postoperative period. We found that long-term neuropathic pain could be adequately reduced by buprenorphine. However, the AD50 in neuropathic pain was significantly higher relative to the AD50 in the short-term postoperative pain, indicating a lower responsiveness of neuropathic pain to opioids. We also found a strict relationship between the short-term and long-term AD50, characterized by a saturating effect. In fact, if the AD50 soon after surgery was low, the AD50 increase in the long-term neuropathic pain was threefold. By contrast, if the AD50 soon after surgery was high, the AD50 in neuropathic pain was only slightly increased. This suggests that, though neuropathic pain is indeed less sensitive to opioids, in some neuropathic patients a large amount of opioid resistance is already present in other painful conditions.

The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression.

Although in most of the cases the placebo response appears to be unpredictable, several factors have been considered in order to explain the placebo analgesic effect. For example, it is widely recognized, albeit with little empirical evidence, that placebo analgesia is more likely to occur after a successful analgesic therapy. On the basis of this assumption, we tested the placebo response in a population of patients who were treated with buprenorphine the day before for relieving postoperative pain. However, due to the high variability of opioid responsiveness, buprenorphine was effective in some patients and poorly effective in some others. Similarly, buprenorphine produced respiratory depression with a large variability, ranging from mild depression to no effect. We found that the placebo analgesic response depended on the buprenorphine analgesic effectiveness of the previous day. Analogously, we found that a placebo respiratory depressant response was more pronounced in those patients with a respiratory depressant response to buprenorphine on the day before, irrespective of the analgesic effectiveness. These specific effects suggest that (1) the placebo effect is experience-dependent; (2) the mechanisms underlying placebo analgesia and placebo respiratory depression are independent from each other and, by considering the role of endogenous opioids in placebo analgesia, might involve different subpopulations of opioid receptors.