Illuminating somatostatin analog action at neuroendocrine tumor receptors

Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin receptor subtypes have been identified and molecular mechanisms of somatostatin receptor signaling and regulation have been elucidated. These advances increased understanding of the biological role of each somatostatin receptor subtype, their distribution in NETs, as well as agonist-specific regulation of receptor signaling, internalization, and phosphorylation, particularly for the sst2 receptor subtype, which is the primary target of current somatostatin analog therapy for NETs. Various hypotheses exist to explain differences in patient responsiveness to somatostatin analog inhibition of tumor secretion and growth as well as differences in the development of tumor resistance to therapy. In addition, we now have a better understanding of the action of both first generation (octreotide, lanreotide, Octreoscan) and second generation (pasireotide) FDA-approved somatostatin analogs, including the biased agonistic character of some agonists. The increased understanding of somatostatin receptor pharmacology provides new opportunities to design more sophisticated assays to aid the future development of somatostatin analogs with increased efficacy.

Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, phase II safety study

PURPOSE: We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma (HCC) that had progressed following first-line sorafenib. PATIENTS AND METHODS: Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child-Pugh class A) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression, unacceptable toxicity, death or patient/physician decision to discontinue. The primary end-point was safety; secondary end-points included efficacy (including time to progression and overall survival). RESULTS: The median treatment duration was 19.5 weeks (range 2-103). At data cutoff, three patients remained on treatment. Reasons for discontinuation were adverse events (n=20), disease progression (n=10), consent withdrawal (n=2) and death (n=1). Seventeen patients required dose reductions (mostly for adverse events [n=15]); 35 patients had treatment interruption (mostly for adverse events [n=32] or patient error [n=11]). The most frequent treatment-related adverse events were hand-foot skin reaction (any grade n=19; grade ≥3 n=5), diarrhoea (n=19; n=2), fatigue (n=19; n=6), hypothyroidism (n=15; n=0), anorexia (n=13; n=0), hypertension (n=13; n=1), nausea (n=12; n=0) and voice changes (n=10; n=0). Disease control was achieved in 26 patients (partial response n=1; stable disease n=25). Median time to progression was 4.3 months. Median overall survival was 13.8 months. CONCLUSION: Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib.

Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors

PURPOSE Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. EXPERIMENTAL DESIGN This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy. RESULTS In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. CONCLUSIONS Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PFT).

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n=95) and Z6P3 (n=95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p=0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. This article is protected by copyright. All rights reserved.

Long-term outcome of patients with clinical stage I high-risk nonseminomatous germ-cell tumors 15 years after one adjuvant cycle of bleomycin, etoposide, and cisplatin chemotherapy

BACKGROUND To report the long-term results of adjuvant treatment with one cycle of modified bleomycin, etoposide, and cisplatin (BEP) in patients with clinical stage I (CS I) nonseminomatous germ-cell tumors (NSGCT) at high risk of relapse. PATIENTS AND METHODS In a single-arm, phase II clinical trial, 40 patients with CS I NSGCT with vascular invasion and/or >50% embryonal cell carcinoma in the orchiectomy specimen received one cycle of adjuvant BEP (20 mg/m(2) bleomycin as a continuous infusion over 24 h, 120 mg/m(2) etoposide and 40 mg/m(2) cisplatin each on days 1-3). Primary end point was the relapse rate. RESULTS Median follow-up was 186 months. One patient (2.5%) had a pulmonary relapse 13 months after one BEP and died after three additional cycles of BEP chemotherapy. Three patients (7.5%) presented with a contralateral metachronous testicular tumor, and three (7.5%) developed a secondary malignancy. Three patients (7.5%) reported intermittent tinnitus and one had grade 2 peripheral polyneuropathy (2.5%). CONCLUSIONS Adjuvant chemotherapy with one cycle of modified-BEP is a feasible and safe treatment of patients with CS I NSGCT at high risk of relapse. In these patients, it appears to be an alternative to two cycles of BEP and to have a lower relapse rate than retroperitoneal lymph node dissection. If confirmed by other centers, 1 cycle of adjuvant BEP chemotherapy should become a first-line treatment option for this group of patients.

Anaesthesiological management of mediastinal tumors

The perioperative management of patients with mediastinal masses is a special clinical challenge in our field. Even though regional anaesthesia is normally the first choice, in some cases it is not feasible due to the method of operation. In these cases general anaesthesia is the second option but can lead to respiratory and haemodynamic decompensation due to tumor-associated compression syndrome (mediastinal mass syndrome). The appropriate treatment begins with the preoperative risk classification on the basis of clinical and radiological findings. In addition to anamnesis, chest radiograph, and CT, dynamical methods (e.g. pneumotachography and echocardiography) should be applied to verify possible intraoperative compression syndromes. The induction of general anaesthesia is to be realized in awake-fiberoptic intubation with introduction of the tube via nasal route while maintaining the spontaneous breathing of the patient. The anaesthesia continues with short effective agents applied inhalative or iv. If possible from the point of operation, agents of muscle relaxation are not to be applied. If the anaesthesia risk is classified as uncertain or unsafe, depending on the location of tumor compression (tracheobronchial tree, pulmonary artery, superior vena cava), alternative techniques of securing the respiratory tract (different tubes, rigid bronchoscope) and cardiopulmonary bypass with extracorporal oxygen supply are prepared. For patients with severe clinical symptoms and extensive mediastinal mass, the preoperative cannulation of femoral vessels is also recommended. In addition to fulfilling technical and personnel requirements, an interdisciplinary cooperation of participating fields is the most important prerequisite for the optimal treatment of patients.

Improved VMAT planning for head and neck tumors with an advanced optimization algorithm

OBJECTIVE In this study, the "Progressive Resolution Optimizer PRO3" (Varian Medical Systems) is compared to the previous version "PRO2" with respect to its potential to improve dose sparing to the organs at risk (OAR) and dose coverage of the PTV for head and neck cancer patients. MATERIALS AND METHODS For eight head and neck cancer patients, volumetric modulated arc therapy (VMAT) treatment plans were generated in this study. All cases have 2-3 phases and the total prescribed dose (PD) was 60-72Gy in the PTV. The study is mainly focused on the phase 1 plans, which all have an identical PD of 54Gy, and complex PTV structures with an overlap to the parotids. Optimization was performed based on planning objectives for the PTV according to ICRU83, and with minimal dose to spinal cord, and parotids outside PTV. In order to assess the quality of the optimization algorithms, an identical set of constraints was used for both, PRO2 and PRO3. The resulting treatment plans were investigated with respect to dose distribution based on the analysis of the dose volume histograms. RESULTS For the phase 1 plans (PD=54Gy) the near maximum dose D2% of the spinal cord, could be minimized to 22±5 Gy with PRO3, as compared to 32±12Gy with PRO2, averaged for all patients. The mean dose to the parotids was also lower in PRO3 plans compared to PRO2, but the differences were less pronounced. A PTV coverage of V95%=97±1% could be reached with PRO3, as compared to 86±5% with PRO2. In clinical routine, these PRO2 plans would require modifications to obtain better PTV coverage at the cost of higher OAR doses. CONCLUSION A comparison between PRO3 and PRO2 optimization algorithms was performed for eight head and neck cancer patients. In general, the quality of VMAT plans for head and neck patients are improved with PRO3 as compared to PRO2. The dose to OARs can be reduced significantly, especially for the spinal cord. These reductions are achieved with better PTV coverage as compared to PRO2. The improved spinal cord sparing offers new opportunities for all types of paraspinal tumors and for re-irradiation of recurrent tumors or second malignancies.

Twelve percent of hips with a primary cam deformity exhibit a slip-like morphology resembling sequelae of slipped capital femoral epiphysis

BACKGROUND In some hips with cam-type femoroacetabular impingement (FAI), we observed a morphology resembling a more subtle form of slipped capital femoral epiphysis (SCFE). Theoretically, the morphology in these hips should differ from hips with a primary cam-type deformity. QUESTIONS/PURPOSES We asked if (1) head-neck offset; (2) epiphyseal angle; and (3) tilt angle differ among hips with a slip-like morphology, idiopathic cam, hips after in situ pinning of SCFE, and normal hips; and (4) what is the prevalence of a slip-like morphology among cam-type hips? METHODS We retrospectively compared the three-dimensional anatomy of hips with a slip-like morphology (29 hips), in situ pinning for SCFE (eight hips), idiopathic cam deformity (171 hips), and 30 normal hips using radial MRI arthrography. Normal hips were derived from 17 asymptomatic volunteers. All other hips were recruited from a series of 277 hips (243 patients) seen at a specialized academic hip center between 2006 and 2010. Forty-one hips with isolated pincer deformity were excluded. Thirty-six of 236 hips had a known cause of cam impingement (secondary cam), including eight hips after in situ pinning of SCFE (postslip group). The 200 hips with a primary cam were separated in hips with a slip-like morphology (combination of positive fovea sign [if the neck axis did not intersect with the fovea capitis] and a tilt angle [between the neck axis and perpendicular to the basis of the epiphysis] exceeding 4°) and hips with an idiopathic cam. We evaluated offset ratio, epiphyseal angle (angle between the neck axis and line connecting the center of the femoral head and the point where the physis meets the articular surface), and tilt angle circumferentially around the femoral head-neck axis. Prevalence of slip-like morphology was determined based on the total of 236 hips with cam deformities. RESULTS Offset ratio was decreased anterosuperiorly in idiopathic cam, slip-like, and postslip (eg, 1 o'clock position with a mean offset ranging from 0.00 to 0.14; p < 0.001 for all groups) compared with normal hips (0.25 ± 0.06 [95% confidence interval, 0.13-0.37]) and increased posteroinferiorly in slip-like (eg, 8 o'clock position, 0.5 ± 0.09 [0.32-0.68]; p < 0.001) and postslip groups (0.55 ± 0.12 [0.32-0.78]; p < 0.001) and did not differ in idiopathic cam (0.32 ± 0.09 [0.15-0.49]; p = 0.323) compared with normal (0.31 ± 0.07 [0.18-0.44]) groups. Epiphyseal angle was increased anterosuperiorly in the slip-like (eg, 1 o'clock position, 70° ± 9° [51°-88°]; p < 0.001) and postslip groups (75° ± 13° [49°-100°]; p = 0.008) and decreased in idiopathic cam (50° ± 8° [35°-65°]; p < 0.001) compared with normal hips (58° ± 8° [43°-74°]). Posteroinferiorly, epiphyseal angle was decreased in slip-like (eg, 8 o'clock position, 54° ± 10° [34°-74°]; p < 0.001) and postslip (44° ± 11° [23°-65°]; p < 0.001) groups and did not differ in idiopathic cam (76° ± 8° [61°-91°]; p = 0.099) compared with normal (73° ± 7° [59°-88°]) groups. Tilt angle increased in slip-like (eg, 2/8 o'clock position, 14° ± 8° [-1° to 30°]; p < 0.001) and postslip hips (29° ± 10° [9°-48°]; p < 0.001) and decreased in hips with idiopathic cam (-7° ± 5° [-17° to 4°]; p < 0.001) compared with normal (-1° ± 5° [-10° to 8°]) hips. The prevalence of a slip-like morphology was 12%. CONCLUSIONS The slip-like morphology is the second most frequent pathomorphology in hips with primary cam deformity. MRI arthrography of the hip allows identifying a slip-like morphology, which resembles hips after in situ pinning of SCFE and distinctly differs from hips with idiopathic cam. These results support previous studies reporting that SCFE might be a risk factor for cam-type FAI.

Influence of contact points on the performance of caries detection methods in approximal surfaces of primary molars: an in vivo study

This in vivo study aimed to evaluate the influence of contact points on the approximal caries detection in primary molars, by comparing the performance of the DIAGNOdent pen and visual-tactile examination after tooth separation to bitewing radiography (BW). A total of 112 children were examined and 33 children were selected. In three periods (a, b, and c), 209 approximal surfaces were examined: (a) examiner 1 performed visual-tactile examination using the Nyvad criteria (EX1); examiner 2 used DIAGNOdent pen (LF1) and took BW; (b) 1 week later, after tooth separation, examiner 1 performed the second visual-tactile examination (EX2) and examiner 2 used DIAGNOdent again (LF2); (c) after tooth exfoliation, surfaces were directly examined using DIAGNOdent (LF3). Teeth were examined by computed microtomography as a reference standard. Analyses were based on diagnostic thresholds: D1: D 0 = health, D 1 –D 4 = disease; D2: D 0 , D 1 = health, D 2 –D 4 = disease; D3: D 0 –D 2 = health, D 3 , D 4 = disease. At D1, the highest sensitivity/specificity were observed for EX1 (1.00)/LF3 (0.68), respectively. At D2, the highest sensitivity/ specificity were observed for LF3 (0.69)/BW (1.00), respectively. At D3, the highest sensitivity/specificity were observed for LF3 (0.78)/EX1, EX2 and BW (1.00). EX1 showed higher accuracy values than LF1, and EX2 showed similar values to LF2. We concluded that the visual-tactile examination showed better results in detecting sound surfaces and approximal caries lesions without tooth separation. However, the effectiveness of approximal caries lesion detection of both methods was increased by the absence of contact points. Therefore, regardless of the method of detection, orthodontic separating elastics should be used as a complementary tool for the diagnosis of approximal noncavitated lesions in primary molars.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

BACKGROUND VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING Eli Lilly and Co.

High intratumoral levels of FoxP3+ lymphocytes are associated with better prognosis in primary resected esophageal adenocarcinomas.

Background: Tumor infiltrating T-lymphocytes (TILs) have been shown to play an important prognostic role in many carcinomas. The identification of prognostic relevant morphological or molecular factors is a major area of interest in the diagnostic process and for the treatment of highly aggressive esophageal adenocarcinoma. Studies about the impact of TILs in this tumor have not shown completely congruent results yet. We present a comprehensive study about the clinical and pathological impact of TIL in esophageal adenocarcinomas. Methods: A next generation tissue microarray (TMA) of 117 primary resected esophageal adenocarcinomas was analyzed for CD3+, CD8+ and FoxP3+ TIL using immunohistochemistry. The TMA contained three cores of the tumor center and the tumor periphery per each case. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio) and an image analysis software (Aperio Image Scope) was used to determine the TIL counts. The results were correlated with clinicopathological parameters. Results: CD3+, CD8+ and FoxP3+ TIL counts showed a significant correlation among each other (p<0.001 each, range: 0.27-0.77). TIL counts were categorized as high and low levels, according to the median. Tumors with high FoxP3+ intratumoral lymphocyte counts were more frequently of lower pT category (p<0.001) and without lymph node metastasis (p=0.04). High levels of FoxP3+ lymphocytes in the tumor center and the periphery were also associated with better prognosis (p<0.001 and p=0.041, respectively) in univariate analysis. A similar prognostic impact was seen for high levels of CD3+ and CD8+ TIL in the tumor center, but not in the periphery (p=0.047 and p=0.011, respectively). In multivariate analysis high central FoxP3+TIL levels were an independent prognostic factor (HR=0.4; p=0.023) which was similar to a combination score of CD3+/CD8+/FoxP3+ TIL (HR=0.54; p=0.027) or CD8+/Foxp3+ TIL (HR=0.052; p=0.020) and superior to pT- and pN category (p>0.05 each). Conclusion: This study demonstrates a significant beneficial prognostic impact of high TIL counts in the tumor center of esophageal adenocarcinomas, in particular with regards to the subpopulation of FoxP3+ and CD8+ T-regulatory cells. The determination of intratumoral lymphocytic counts and application of TIL scores can improve prognostic accuracy of pathologic reports of these tumors and may be helpful for better risk stratification of esophageal adenocarcinoma patients.

Primary forest dynamics in lowland dipterocarp forest at Danum Valley, Sabah, Malaysia, and the role of the understorey

Changes in species composition in two 4–ha plots of lowland dipterocarp rainforest at Danum, Sabah, were measured over ten years (1986 to 1996) for trees greater than or equal to 10 cm girth at breast height (gbh). Each included a lower–slope to ridge gradient. The period lay between two drought events of moderate intensity but the forest showed no large lasting responses, suggesting that its species were well adapted to this regime. Mortality and recruitment rates were not unusual in global or regional comparisons. The forest continued to aggrade from its relatively (for Sabah) low basal area in 1986 and, together with the very open upper canopy structure and an abundance of lianas, this suggests a forest in a late stage of recovery from a major disturbance, yet one continually affected by smaller recent setbacks. Mortality and recruitment rates were not related to population size in 1986, but across subplots recruitment was positively correlated with the density and basal area of small trees (10 to <50 cm gbh) forming the dense understorey. Neither rate was related to topography. While species with larger mean gbh had greater relative growth rates (rgr) than smaller ones, subplot mean recruitment rates were correlated with rgr among small trees. Separating understorey species (typically the Euphorbiaceae) from the overstorey (Dipterocarpaceae) showed marked differences in change in mortality with increasing gbh: in the former it increased, in the latter it decreased. Forest processes are centred on this understorey quasi–stratum. The two replicate plots showed a high correspondence in the mortality, recruitment, population changes and growth rates of small trees for the 49 most abundant species in common to both. Overstorey species had higher rgrs than understorey ones, but both showed considerable ranges in mortality and recruitment rates. The supposed trade–off in traits, viz slower rgr, shade tolerance and lower population turnover in the understorey group versus faster potential growth rate, high light responsiveness and high turnover in the overstorey group, was only partly met, as some understorey species were also very dynamic. The forest at Danum, under such a disturbance–recovery regime, can be viewed as having a dynamic equilibrium in functional and structural terms. A second trade–off in shade–tolerance versus drought–tolerance is suggested for among the understorey species. A two–storey (or vertical component) model is proposed where the understorey–overstorey species’ ratio of small stems (currently 2:1) is maintained by a major feedback process. The understorey appears to be an important part of this forest, giving resilience against drought and protecting the overstorey saplings in the long term. This view could be valuable for understanding forest responses to climate change where drought frequency in Borneo is predicted to intensify in the coming decades.

PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia.

Symptoms of primary ciliary dyskinesia (PCD) are nonspecific and guidance on whom to refer for testing is limited. Diagnostic tests for PCD are highly specialised, requiring expensive equipment and experienced PCD scientists. This study aims to develop a practical clinical diagnostic tool to identify patients requiring testing.Patients consecutively referred for testing were studied. Information readily obtained from patient history was correlated with diagnostic outcome. Using logistic regression, the predictive performance of the best model was tested by receiver operating characteristic curve analyses. The model was simplified into a practical tool (PICADAR) and externally validated in a second diagnostic centre.Of 641 referrals with a definitive diagnostic outcome, 75 (12%) were positive. PICADAR applies to patients with persistent wet cough and has seven predictive parameters: full-term gestation, neonatal chest symptoms, neonatal intensive care admittance, chronic rhinitis, ear symptoms, situs inversus and congenital cardiac defect. Sensitivity and specificity of the tool were 0.90 and 0.75 for a cut-off score of 5 points. Area under the curve for the internally and externally validated tool was 0.91 and 0.87, respectively.PICADAR represents a simple diagnostic clinical prediction rule with good accuracy and validity, ready for testing in respiratory centres referring to PCD centres.