Search

Prior skin image datasets have not addressed patient-level information obtained from multiple skin lesions from the same patient. Though artificial intelligence classification algorithms have achieved expert-level performance in controlled studies examining single images, in practice dermatologists base their judgment holistically from multiple lesions on the same patient. The 2020 SIIM-ISIC Melanoma Classification challenge dataset described herein was constructed to address this discrepancy between prior challenges and clinical practice, providing for each image in the dataset an identifier allowing lesions from the same patient to be mapped to one another. This patient-level contextual information is frequently used by clinicians to diagnose melanoma and is especially useful in ruling out false positives in patients with many atypical nevi. The dataset represents 2,056 patients (20.8% with at least one melanoma, 79.2% with zero melanomas) from three continents with an average of 16 lesions per patient, consisting of 33,126 dermoscopic images and 584 (1.8%) histopathologically confirmed melanomas compared with benign melanoma mimickers., Measurement(s) melanoma • Skin Lesion Technology Type(s) Dermoscopy • digital curation Factor Type(s) approximate age • sex • anatomic site Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.13070345

There is optimism that artificial intelligence (AI) will result in positive clinical outcomes, which is driving research and investment in the use of AI for skin disease. At present, AI for skin disease is embedded in research and development and not practiced widely in clinical dermatology. Clinical dermatology is also undergoing a technological transformation in terms of the development and adoption of standards that optimizes the quality use of imaging. Digital Imaging and Communications in Medicine (DICOM) is the international standard for medical imaging. DICOM is a continually evolving standard. There is considerable effort being invested in developing dermatology-specific extensions to the DICOM standard. The ability to encode relevant metadata and afford interoperability with the digital health ecosystem (e.g., image repositories, electronic medical records) has driven the initial impetus in the adoption of DICOM for dermatology. DICOM has a dedicated working group whose role is to develop a mechanism to support AI workflows and encode AI artifacts. DICOM can improve AI workflows by encoding derived objects (e.g., secondary images, visual explainability maps, AI algorithm output) and the efficient curation of multi-institutional datasets for machine learning training, testing, and validation. This can be achieved using DICOM mechanisms such as standardized image formats and metadata, metadata-based image retrieval, and de-identification protocols. DICOM can address several important technological and workflow challenges for the implementation of AI. However, many other technological, ethical, regulatory, medicolegal, and workforce barriers will need to be addressed before DICOM and AI can be used effectively in dermatology.

Patients with acute myeloid leukemia (AML), who are refractory to induction therapy or experience relapse after a first complete remission (CR), have an unfavorable prognosis.[1][1] Epigenetic dysregulation is frequent in AML. In preclinical studies, the pan-deacetylase inhibitor (DACi) panobinostat

Background Dysregulated autobiographical recall is observed in major depressive disorder (MDD). However, it is unknown whether people with MDD show abnormalities in memory-, emotion-, and control-related brain systems during reactivity to and regulation of negative autobiographical memories. Methods We used functional magnetic resonance imaging to identify neural mechanisms underlying MDD-related emotional responses to negative autobiographical memories and the ability to downregulate these responses using a cognitive regulatory strategy known as reappraisal. We compared currently depressed, medication-free patients with MDD ( n = 29) with control participants with no history of depression ( n = 23). Results Relative to healthy control participants, medication-free MDD patients reported greater negative emotion during recall but relatively intact downregulation success. They also showed elevated amygdala activity and greater amygdala-hippocampal connectivity. This connectivity mediated the effect of MDD on negative emotional experience. When reappraising memories (vs. recalling from an immersed perspective), the MDD and control groups showed comparable recruitment of the prefrontal, parietal, and temporal cortices, and comparable downregulation of the amygdala and anterior hippocampus. However, MDD patients showed greater downregulation of the posterior hippocampus, and the extent of this downregulation predicted successful reduction of negative affect in MDD patients only. Conclusions These data suggest amygdala-hippocampal connectivity and posterior hippocampal downregulation as brain mechanisms related to elevated emotional reactivity and atypical emotion regulation in MDD.

How a visual stimulus is initially categorized as a face by the cortical face-processing network remains largely unclear. In this study we used functional MRI to study the dynamics of face detection in visual scenes by using a paradigm in which scenes containing faces or cars are revealed progressively as they emerge from visual noise. Participants were asked to respond as soon as they detected a face or car during the noise sequence. Among the face-sensitive regions identified based on a standard localizer, a high-level face-sensitive area, the right fusiform face area (FFA), showed the earliest difference between face and car activation. Critically, differential activation in FFA was observed before differential activation in the more posteriorly located occipital face area (OFA). A whole brain analysis confirmed these findings, with a face-sensitive cluster in the right fusiform gyrus being the only cluster showing face preference before successful behavioral detection. Overall, these findings indicate that following generic low-level visual analysis, a face stimulus presented in a gradually revealed visual scene is first detected in the right middle fusiform gyrus, only after which further processing spreads to a network of cortical and subcortical face-sensitive areas (including the posteriorly located OFA). These results provide further evidence for a nonhierarchical organization of the cortical face-processing network.

Nowadays, lumbar spondylosis is one of the most frequent causes of lower back pain. In order to improve our understanding of the lumbar spine anatomy and functionality over time, we compared the lumbar vertebrae of Neanderthals with those of anatomically modern humans. The fossil record reports on only two Neanderthal skeletons (i.e., Kebara 2 and Shanidar 3, both predating the appearance of modern humans) with full preservation of the entire lumbar spine. Examination of these early hominids showed that they display natural lumbar kyphosis, with only mild degenerative changes of the lumbar spine (ages at death: 30-35 years, Kebara 2; and 35-50 years, Shanidar 3). This finding is highly unexpected since Neanderthals are known to have had extraordinary physical activity due to demanding living conditions. The adult lumbar spines discussed here therefore show no correlation between high physical activity and degenerative spine disease as known from recent times. We speculate that both the kyphosis itself and the massive and heavily muscled skeleton of Neanderthals are causative for the minimal bone degeneration. We conclude that a kyphotic lumbar spine is the natural anatomy in these two Neanderthal individuals. Future research will reveal if this holds true for the entire Neanderthal species.

An easy to use method for an approximate creep life prediction for pipe bends was developed within a recent R & D-project in Germany. The new algorithm is based on a Finite-Element parameter study comprising approximately 200 pipe bends. The creep behaviour of the materials primarily used for main steam and hot reheat piping is described using the Graham–Walles creep law. Since the new algorithm considers the time dependent out-of-roundness and stress redistribution of the pipe bend, it yields a more precise creep life prediction, compared to standard piping codes. It is possible to integrate this new calculation into existing online lifetime-monitoring-systems.

✓ Spinal tuberculosis (TB) infrequently involves more than one to three vertebrae, and kyphotic angulation of greater than 30° is rare in paleopathological specimens and clinical studies. The authors describe findings obtained in two spines (dating from the Early and Late Middle Ages). Spinal TB was present in both as well as sharply angulated kyphosis (∼ 180°) resulting from complete destruction of five and seven vertebral bodies, respectively. In these two specimens obtained in individuals older than 12 years of age at the time of death we observed no involvement of the disease in posterior vertebral elements, and the laminae showed osseous fusion without signs of infection. The osseous diameter of the spinal canal was not narrowed in either case. These findings are discussed in the context of modern medical knowledge and paleopathological and genetic examinations.

Cystic meningiomas are uncommon tumors that are easily confused with metastatic or glial tumors with cystic components. We report on our experience of intraoperative findings and management of peritumoral cyst wall and cyst fluid in cystic meningiomas. We reviewed all the meningiomas operated on at our department in a 3 1/2-year period (January 1998 to June 2001). Pathological and intraoperative findings of cystic meningiomas compared to noncystic meningiomas are examined. There were 111 cases of intracranial meningiomas operated on, including seven cystic meningiomas (6.3%). In six cases, we found peritumoral cyst configurations. The tumor locations of cystic meningiomas were the cerebral convexity and sphenoid ridge. One peritumoral cyst formation had meningioma cells in the cyst wall. Cytologic examination of the cystic fluid displayed the presence of meningiothelial cells in one case. In one case, intraoperative findings and pathological examination provided the diagnosis of two differently located meningiomas in one cyst configuration, its walls lined by clear arachnoid. Four of the seven cases had peritumoral cystic meningiomas of the atypical type according to the WHO classification. One case with intratumoral cyst configuration was associated with the anaplastic type (WHO degrees 3). Intraoperative biopsies and histopathological studies of the cyst wall are recommended in peritumoral cystic meningiomas. Our observations suggest that cystic meningiomas have the potential to spread through cystic fluid to the cystic wall in peritumoral cyst configuration. The follow-up intervals should be short in cystic meningiomas.

Differences in popularity are a key aspect of status in virtually all human groups and shape social interactions within them. Little is known, however, about how we track and neurally represent others' popularity. We addressed this question in two real-world social networks using sociometric methods to quantify popularity. Each group member (perceiver) viewed faces of every other group member (target) while whole-brain functional MRI data were collected. Independent functional localizer tasks were used to identify brain systems supporting affective valuation (ventromedial prefrontal cortex, ventral striatum, amygdala) and social cognition (dorsomedial prefrontal cortex, precuneus, temporoparietal junction), respectively. During the face-viewing task, activity in both types of neural systems tracked targets' sociometric popularity, even when controlling for potential confounds. The target popularity-social cognition system relationship was mediated by valuation system activity, suggesting that observing popular individuals elicits value signals that facilitate understanding their mental states. The target popularity-valuation system relationship was strongest for popular perceivers, suggesting enhanced sensitivity to differences among other group members' popularity. Popular group members also demonstrated greater interpersonal sensitivity by more accurately predicting how their own personalities were perceived by other individuals in the social network. These data offer insights into the mechanisms by which status guides social behavior.

Primary intraosseous calvarial meningiomas are very rare entities in recent times. We present the first case in antiquity of a primary intraosseous meningioma in the frontoparietal bone associated with the coronal suture, and discuss its pathology. The skull derives from southwestern Germany and is dated to the 12th–14th centuries AD. The lesion is interpreted as a solitary osteoblastic neoplasm with hyperostosis on the outside, and osteolysis and radial spiculation in the central part of the lesion with an area of irregularity along the inner table. In cases of solitary osteoblastic skull lesions the differential diagnosis comprises: fibrous dysplasia, osteoma, osteoblastic metastasis, Pagets disease and meningioma with sheet-like growth along the dural surface with marked hyperostosis (called meningioma en plaque). We believe that a differentiation between hyperostotic meningioma en plaque and intraosseous meningioma cannot be made in skulls from antiquity. Copyright © 2002 John Wiley & Sons, Ltd.

Excess morbidity and mortality among long-term hemodialysis patients because of infectious complications is partly caused by an impairment of cellular immune defense. We hypothesized this impairment is related to an abnormal carnitine metabolism also present in these patients. In a double-blind, randomized, placebo-controlled trial, we investigated the effect of L-carnitine on phagocytic function and viability of blood leukocytes in 17 patients undergoing maintenance hemodialysis. After an observation period of 1 month, the patients received either 10 mg/kg of L-carnitine or placebo intravenously at the end of each hemodialysis session over a period of 4 months. Leukocyte oxidative metabolism was measured by means of luminol-enhanced chemiluminescence and superoxide generation after stimulation with Staphylococcus aureus or phorbol myristate acetate. Killing capacity and phagocytosis of radiolabeled staphylococci were determined. A lactate dehydrogenase (LDH) release test was applied to assess cell viability. We were unable to show an effect of L-carnitine on phagocytic function and viability in vivo. Several clinical parameters were observed during the trial. No statistically significant differences concerning dialysis-related morbidity, anemia, or reduction of blood urea nitrogen and creatinine levels were detected. Additionally, we tested the effect of L-carnitine on phagocytic function after in vitro incubation of blood leukocytes, which also showed no changes. LDH release was decreased, indicating an improved viability of these cells. The latter results were found after in vitro incubation of cells, but could not be confirmed in vivo. In summary, we could not show beneficial effects of L-carnitine administration in hemodialysis patients for the dosage and duration of treatment stated, either on phagocytic function and viability or on the clinical and biochemical parameters observed.

The intentional deformation of human skulls in the living being was one of the most curious rituals performed in historical and ancient times. It is thought that these practices cause chronic elevated intracranial pressure and subsequent symptoms of cognitive impairment. In this report, we examine such an artificially deformed skull dating from the sixteenth century that in addition shows a fronto-ethmoidal encephalocele. However, although the mild encephalocele was already manifest at birth and deformation practices were performed over years, the encephalocele did not progress into a more severe status. We conclude that the intentional deformation of skulls does not lead to chronic elevated intracranial pressure and mental retardation.

We have realized and investigated Au/Ge/Ni alloyed ohmic contacts to two-dimensional electron systems (2DES) embedded in various Al 0.67 Ga 0.33 As / GaAs heterostructures. Transport and geometrical investigations have been carried out to understand fundamental properties of these contacts. A recipe for creating low resistive and reliable alloyed ohmic contacts to 2DES is given, which is successful even for contacts to deep lying 2DES and contact sizes down to submicron length scale ( 0.2 μ m ). The contact resistance between 2DES and alloyed metal depends on the length and orientation of the interface line between 2DES and alloyed metal relative to the crystal orientation of the heterostructure.

WE EXAMINED SPECIAL pathological changes of the lumbar spine from skeleton remains referred to as "Stetten 1," one of the earliest specimens of modern humans dating from the Early Stone Age (Upper Paleolithic). The skeleton was discovered during archaeological excavations under Riek in 1931 in the Vogelherd Cave near Stetten, close to the Lone Valley of southwestern Germany. The archaeological context is the so-called Aurignacian period (40,000-30,000 yr ago), representing the earliest cultural step of modern humans in Europe. Accelerator mass spectrometry with (14)C measurement yields a calibrated age of these remains averaging 34,100 years before the present. The L3-L4 vertebrae exhibit marginal bone fusion on the right side with a smooth surface. They show 20- to 30-degree kyphosis secondary to wedge impaction of the L4 vertebral body. The facet joints and vertebral bodies reveal small marginal osteophytes with even joint surfaces, indicating low degenerative changes. Stetten 1 is characterized by the presence of a healed lumbar spine fracture. It documents the earliest known case thus far of spine fracture among modern humans.

The use of low-calcium peritoneal dialysis solutions (PDS) for continuous ambulatory peritoneal dialysis is becoming widely accepted to reduce the risk of serum hypercalcemia in patients taking calcium salts as phosphate binders. We compared the in vitro effects of low-calcium PDS (1,000 μmol calcium/L), calcium-free buffer, and buffers with increasing calcium concentrations (500 to 5,000 μmol calcium/L) on peritoneal macrophage (PMO) functions. Peritoneal macrophages isolated from 10 continuous ambulatory peritoneal dialysis patients were incubated in the different solutions and tested for phagocytic and killing capacity, superoxide generation (cytochrome-C reduction and lucigenin-enhanced chemiluminescence), and the rate of myeloperoxidase-dependent oxidative metabolism (luminol-enhanced chemiluminescence). All functions of the PMO incubated in calcium-free buffer were significantly suppressed compared with the PMO incubated in calcium buffers. No dose-dependent increase of a single PMO function could be found after incubating the PMO in calcium buffer with increasing concentrations. Incubation of PMO in otherwise identical PDS containing 1,000, 1,450, or 1,750 μmol calcium/L did not result in significantly different PMO functions. Acidic PDS (pH 5.3 to 5.5) suppressed all measured PMO functions as compared with their neutralized counterparts (pH 7.4), irrespective of the calcium concentration. Results of our in vitro study show that low-calcium PDS does not suppress PMO functions any more than standard-calcium PDS (1,750 μmol calcium/L) does.

Objective To determine the natural history of a surgically placed Tenckhoff catheter in patients on continuous ambulatory peritoneal dialysis (CAPD). Design Prospective 7–year study analyzing catheter survival of all catheters using the Kaplan-Meier life table methodology. Setting Teaching hospital, department of nephrology. Patients One hundred and fifteen unselected patients beginning CAPD. Interventions Removal of the catheter required for the following complications: exit-site or tunnel infections or relapsing peritonitis, outflow obstruction, pericatheter leak, and development of hernias. Main Outcome Measures Period between insertion and removal of the catheter. Results The cumulative survival of all catheters after 1,2, and 3 years of CAPD was 87%, 69% and 65%. Catheter survival of the first versus the second catheter after 1 year was significantly longer (p=0.03). The difference was not significant in relation to diabetes, age, and sex. Infectious complications caused 61% (n=19) of all 31 catheter failures, mainly due to tunnel infections caused by Staphylococcus aureus (n=12). “Mechanical” complications accounted for 49% (n=12) of catheter failures. Eight of 12 mechanical complications were outflow failures. Seven patients had to be transferred to hemodialysis. Conclusions The straight Tenckhoff catheter is a reliable peritoneal access device for CAPD in an unselected patient population.

The spinal nerve can be pinched between the transverse process of the fifth lumbar vertebra and the sacral ala. The patients are divided into two types: elderly persons with degenerative scoliosis and somewhat younger adults with isthmic spondylolisthesis. For the first time, we describe extraforaminal impingement of the spinal nerve in transitional lumbosacral segment with unilateral transverse process anomaly. Selective nerve root blocks were performed in two clinical cases. One patient underwent nerve root decompression via a posterior approach. One year after operation, this patient reported no radicular or lumbar pain. The pathoanatomical study demonstrated pseudoarthrosis between the transverse process and the ala of the sacrum and showed dysplastic facet joints at the level below the transitional vertebra in all specimens. Furthermore, we present the oldest illustration of this pathological condition, published in a book by Carl Wenzel in 1824. Extraforaminal entrapment of the spinal nerve in transitional lumbosacral segment with unilateral transverse process anomaly can cause radiculopathy, and osteophytes are the cause of the entrapment. Dysplastic facet joints on the level below the transitional vertebra could be one reason for “micromotion” resulting in pseudoarthrosis with osteophytes. Sciatica relief was obtained by means of selective nerve root blocks or posterior decompression via a dorsomedial approach.

Udgivelsesdato: June BACKGROUND: Ciclesonide is a new inhaled corticosteroid (ICS). Information about its clinical efficacy and safety in relation to other ICS in children is needed for clinical positioning. OBJECTIVE: This 12-week, randomized, double-blind, double-dummy, three-arm, parallel-group study compared the efficacy and safety of ciclesonide with fluticasone propionate in children with mainly moderate and severe persistent asthma. METHODS: Seven hundred and forty-four patients (aged 6-11years) were randomized to ciclesonide (80 or 160mug once daily) or fluticasone propionate (88mug twice daily), following a 2-4-week run-in. Efficacy measurements included forced expiratory flow in 1s (FEV(1)), morning peak expiratory flow (PEF), asthma symptom scores, rescue medication use and quality of life. Systemic effect was assessed by 24-hour urine free cortisol adjusted for creatinine. RESULTS: FEV(1) and morning PEF increased from baseline in all groups (p

OBJECTIVE Trauma and degenerative joint disease are the most common pathological conditions observed in archaeological skeletal remains. We describe the prevalence of different types of cervical bone diseases observed in the early Middle Ages (6th to 8th centuries AD). METHODS Human skeletons were excavated from Germanic row graves in southwestern Germany. One hundred ninety-six cervical spines thus obtained were examined for bone disease. The degenerative changes were classified into Grades 1 (marginal osteophytes), 2 (uneven joint surfaces), and 3 (osseous ankylosis). Cervical spinal canal stenosis was defined as anteroposterior diameters of RESULTS Of the skeletons, 27.5% demonstrated degenerative changes of the cervical spine. The mean age of the skeletons at the time of death was 33.4 years, compared with 43.7 years for those with degenerative disease. Degenerative changes of the vertebral bodies (usually Grades 1 and 2) were most common in the C5–C6 (12.4%, P < 0.05) and C6–C7 (15.3%, P < 0.05) segments. The medial (6.1%) and lateral (0.6%) atlantoaxial joints were rarely involved in degenerative disease. The facet joints from C3–C4 to C6–C7 demonstrated degenerative changes (usually Grades 1 and 2) in 8.0 to 11.8% of cases. The C2–C3 facet joints were significantly involved in degenerative disease in 19.7% of cases (P < 0.05), one-fourth of which demonstrated osseous ankylosis. We observed cervical spinal canal stenosis in 5 skeletons (2.6%) and osseous intervertebral foraminal stenoses in 12 (6.1%). Isolated cases of other pathological processes, i.e., spondylitis ankylopoietica, occipitalization of the atlas and axis, and an odontoid fracture with pseudoarthrosis, were also recorded. CONCLUSION In the early Middle Ages, the prevalence of degenerative cervical spine disease was the same as that observed today. The C2–C3 facet joints demonstrated high rates of degenerative disease.

Approximately 10% (33 of 304) of the predominantly male skulls from the 6th through 8th centuries in southwestern Germany exhibit cranial fractures derived from blunt or sharp force trauma. No evidence of fracture healing characterizes 24% (n = 8) of these individuals. All nonhealed fractures were caused by sharp force, and four of these wounds cross the sagittal sinus. The lengths of these straight-edged wounds, produced exclusively by sword blows, measure around 8.0 cm for fatal, and about 5.0 cm for nonfatal wounds. Seventy-six percent (n = 25) of these skulls exhibit some healing, which indicates that these injuries did not lead to immediate death. In this group are all depressed fractures resulting from blunt force blows. Two thirds of the 45 cranial injuries noted on these 33 skulls are located on the left side of these individuals, with a concentration in the frontoparietal region. Bony indications of wound infection occur in four cases (12%). Three crania exhibit circular trepanations in association with fractures. These phenomena are discussed in the context of modern neurotraumatological knowledge.

e18572^ Background: Multiple myeloma (MM) is an incurable disease, and significant unmet need remains in the relapsed (Rel) and refractory (Ref) settings. Thus, effective agents and combination strategies are of continued interest. Clinical activity was observed in a phase Ib study of the novel pan-deacetylase inhibitor panobinostat (PAN) and the proteasome inhibitor bortezomib (BTZ) in patients (pts) with Rel or Rel/Ref MM. We report the results of a blinded safety analysis from PANORAMA 1, an international, randomized, double-blind, phase III study of PAN (or placebo) + BTZ + dexamethasone (Dex). Methods: Pts with Rel or Rel/Ref MM (1-3 prior lines of therapy) were enrolled. Pts with BTZ-ref MM were not eligible. The study was comprised of 2 treatment phases, and follow up was to be continued during and after treatment until progressive disease or relapse. Treatment phase 1 consisted of eight 3-week cycles of PAN or placebo administered thrice weekly and BTZ administered twice weekly for 2 weeks. Dex was administered on days of and after BTZ. Pts who achieved clinical benefit proceeded to treatment phase 2, which consisted of four 6-week cycles with BTZ and Dex administered at a reduced frequency. Results: Preliminary demographic and blinded safety data from 536 randomized pts were available with treatment ongoing in 257 pts (47.9%). Median age was 63 years (32-84 y). Approximately half of pts (51.7%) received 2-3 prior lines of therapy and 57.3% received prior stem cell transplant. Any-grade adverse events (AEs) included thrombocytopenia (47.6%), diarrhea (45.7%), fatigue (32.6%), anemia (30.5%), constipation (24.8%), and nausea (24.4%). Common grade 3/4 AEs were thrombocytopenia (36.2%), diarrhea (14.5%), anemia (13.0%), fatigue (12.2%), neutropenia (11.4%), and hypokalemia (11.0%). Of interest, peripheral neuropathy was observed in 24.6% at any grade and 5.3% at grade 3/4. Conclusions: Preliminary analysis in 525 pts treated in PANORAMA 1 demonstrated a comparable safety profile to clinical experience with BTZ + Dex. The data monitoring committee recommended the study continue as planned. Enrollment completion is anticipated for Feb 2012 (N = 762). Updated blinded safety data will be presented.

Abstract 3976 Background: The outcomes of patients with multiple myeloma (MM) have significantly improved in recent years mainly because of the availability of 2 novel classes of drugs: immunomodulatory drugs (IMiDs; thalidomide and lenalidomide) and proteasome inhibitors (bortezomib). However, a subset of MM patients is refractory to these agents, and responding patients often relapse or progress. Therefore, novel salvage treatments are needed. Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that has demonstrated synergy in combination with bortezomib in preclinical MM studies. This synergy is thought to occur through inhibition of protein metabolism via targeting of the aggresome and proteasome pathways. Significant clinical activity, including complete responses, was observed in a phase Ib study of panobinostat + bortezomib in patients with relapsed or relapsed and refractory MM (San-Miguel et al, EHA 2011, abstract 0314). In addition, responses were observed in patients with bortezomib-refractory MM. Based on these preliminary data, a phase II and III clinical study program of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed or refractory MM was initiated—PANobinostat ORAl in Multiple myelomA (PANORAMA). PANORAMA 1 is an international, randomized, double-blind, phase III study of panobinostat (or placebo) + bortezomib + dexamethasone. PANORAMA 2 is a single-arm, open-label, phase II study in bortezomib-refractory patients conducted in the United States. Preliminary response data from PANORAMA 2 were available in 20 patients, and met the predefined threshold allowing, together with early tolerability data, continuation and completion of study enrollment (Schlossman et al, EHA 2011, abstract 0900). Here we present the preliminary demographic and blinded safety results of the phase III study (PANORAMA 1) in patients with relapsed MM. Methods: A total of 672 patients with relapsed or relapsed and refractory MM (1–3 prior lines of therapy) will be enrolled to the trial. Patients with prior bortezomib-based therapy are eligible; however, patients with bortezomib-refractory MM (not achieving at least a minimal response or progressed on or within 60 days of the last bortezomib-containing regimen) are excluded from this trial. PANORAMA 1 comprises 2 treatment phases. Treatment phase 1 consists of eight 3-week cycles of panobinostat (oral 20 mg) or placebo administered thrice weekly and bortezomib (intravenous 1.3 mg/m2) administered twice weekly, each for 2 of 3 weeks. Dexamethasone (oral 20 mg) is administered on the days of and after bortezomib dosing. If clinical benefit is observed, patients proceed to treatment phase 2, which consists of four 6-week cycles with a modified (once-weekly) bortezomib schedule. The primary endpoint is progression-free survival, and the key secondary endpoint is overall survival. Results: Blinded data from 273 enrolled patients in a planned safety analysis are available (data cutoff 31 January 2011). Median age was 64 years (range 32–79 years), and 45% of patients were ≥ 65 years of age. Approximately half of the patients (51%) had received 1 prior line of therapy, whereas 49% received 2–3 prior lines of therapy. Most patients (60%) had also received prior stem cell transplantation. Previous treatment included thalidomide (35%), bortezomib (32%), and lenalidomide (14%). Preliminary pooled safety data (blinded) were available in 267 patients who received 1 dose of treatment. The most commonly affected organ class was the gastrointestinal system (all grade, 59% vs grade 3/4, 15.4%), of which diarrhea was most common (all grade, 36% vs grade 3/4, 10%). Other common AEs (all grade vs grade 3/4) were thrombocytopenia (41% vs 29%), anemia (24% vs 10%), fatigue (24% vs 9%), and neutropenia (12% vs 8%). Peripheral neuropathy of any grade was observed in 19% of patients, with grade 3/4 observed in 3% of patients. Conclusions: Panobinostat in combination with bortezomib has shown clinical activity in relapsed and refractory MM patients. Preliminary analysis of pooled safety data (blinded) from the first 267 patients treated in PANORAMA 1 demonstrated no new or unexpected AEs. Updated demographics and safety data for approximately 500 patients will be presented. The results of PANORAMA 1 and PANORAMA 2 will help determine the potential role of panobinostat in the treatment of patients with relapsed and refractory MM. Disclosures: San-Miguel: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yoon:Celgene: Consultancy; NK Bio: Consultancy. Wiktor-Jedrzejczak:Janssen-Cilag Polska: Honoraria; Novartis: Research Funding. Siritanaratkul:Novartis: Research Funding. Dimopoulos:Novartis: Consultancy, Honoraria. Corradini:Celgene: Honoraria; Genzyme: Honoraria. Günther:Novartis: Consultancy, Research Funding; Celgene: Consultancy. Yong:Janssen-Cilag UK: Honoraria. Wroclawska-Swacha:Novartis: Employment. Weber:Novartis: Employment, Equity Ownership. Bourquelot:Novartis: Employment, Equity Ownership. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Einsele:Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy. Moreau:Novartis: Honoraria. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

TPS227 Background: The development of novel agents, including the proteasome inhibitor bortezomib (BTZ), has resulted in significant improvements in survival for patients (pts) with multiple myelom...

In a retrospective study we reviewed upright chest x-ray films of 101 continuous ambulatory peritoneal dialysis (CAPD) patients to determine the incidence and significance of free subdiaphragmal air. A pneumoperitoneum (PP) was diagnosed if a minimal shadow of free air was detected under the diaphragm. The amount of free air was determined by measuring the height and width of the subdiaphragmal air shadow. Of all CAPD patients, 33.6% (34 of 101) had at least one occurrence of PP. Thirteen of these 34 patients (38.2%) were diagnosed within 30 days after catheter implantation, 10 patients (29.5%) acquired a PP during an episode of peritonitis, and in 11 patients (32.4%) no additional risk factor could be determined. Patients radiographed within 30 days after catheter implantation showed a statistically significant higher incidence of PP compared with the same patients radiographed later (22% v 10%; P0.05). The incidence of PP in CAPD patients suffering from peritonitis (33%) was significantly higher than in patients without peritonitis (10%; P0.001). The amount of free air did not differ statistically significantly between the investigated groups. Only two patients with PP and peritonitis had surgically confirmed visceral perforation. Therefore, the main reason for PP seemed to be handling faults during CAPD bag exchange. There was no correlation between the organisms causing peritonitis and PP or the CAPD connector system and PP. In conclusion, a PP occurs in approximately one third of all CAPD patients and a visceral perforation cannot be diagnosed by the occurrence and amount of free subdiaphragmal air.

Skin biopsies of 33 uremic patients-13 patients on continuous ambulatory peritoneal dialysis (CAPD), 12 on hemodialysis (HD), 8 patients with end-stage renal disease (ESRD) before initiation of dialysis treatment-and 10 healthy volunteers were investigated to determine the number of Langerhans cells (LC) by light microscopy after staining for S-100 protein. The epidermal LC count was significantly lower in patients on CAPD (mean: 62.9 LC/mm2; p = 0.027) and patients on HD (mean: 30.4 LC/mm2; p = 0.0015) compared to controls (mean: 110.1 LC/mm2) and uremic patients before initiation of dialysis treatment (mean: 122.6 LC/mm2). The difference between LC counts of CAPD and HD patients did not reach statistical significance (p = 0.057). There was no relation between LC count and age (p = 0.057) or epidermal width (p = 0.26). No statistically significant correlation could be demonstrated between duration of dialysis and LC count (r = -0.33, p = 0.10). LC counts of CAPD patients with diabetes mellitus (n = 7) were not significantly different from those of nondiabetics (n = 6; p = 0.77). LC counts seem to be normal in uremic patients before dialysis treatment. The reduction in LC density in the skin of dialysis patients may contribute to immunodeficiency of uremic patients on regular dialysis treatment.

TPS276 Background: Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor (pan-DACi) targeting epigenetic and nonepigenetic oncogenic pathways. In preclinical studies with AML cell lines and patient (pt) blast cells, PAN potentiated the activity of ARA-C and fludarabine and was synergistic in combination with doxorubicin. Combining PAN with an active cytotoxic chemotherapy (CT) regimen can potentially improve therapeutic outcomes of and be safely administered to pts with AML who have relapsed or are refractory to prior induction therapy. This phase Ib, multicenter, open-label, dose-finding study comprises two phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with ARA-C and MT (an active and representative regimen in the salvage setting of AML), and a subsequent dose-expansion phase to assess safety and preliminary anti-leukemic activity (FPFV Aug 9, 2009). Methods: Adult pts with AML (WHO criteria) relapsed after 1 prior induction regimen or refr...

TPS282 Background: The demethylating agent 5-Aza is an integral therapy in MDS and AML, in which epigenetic modifications contributing to disease are well-documented. Despite an overall survival benefit, better and earlier responses are needed. Combination of a demethylating agent and a deacetylase inhibitor (DACi) is a rational strategy to reverse aberrant epigenetic alterations and the malignant phenotype. Preclinical data indicate that sequential treatment with demethylating agents and DACi targets multiple mechanisms to synergistically de-repress silenced genes and exert antileukemic activity. Panobinostat (PAN; LBH589) is a potent pan-DACi that has demonstrated antileukemic activity in patients (pts) with AML and MDS. This phase Ib, open-label, multicenter, dose-finding study comprises 2 phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with standard dose 5-Aza, and a subsequent expansion phase to further evaluate safety, tolerability, and antileukemi...

A technique for the fabrication of single-electron transistors (SETs) on tips for use in scanning probe microscopy is presented. The tips are micromachined out of an MBE-grown AlGaAs-GaAs heterostructure with a trench within each tip. The SETs are produced by aluminum evaporation and oxidation, and natural shadowing by the trench is used to separate the source and drain electrodes. By separating adjacent tips also by trenches, the concept allows the fabrication of tip arrays for parallel probing.

In vivo effect of 1,25-dihydroxyvitamin D 3 on phagocyte function in hemodialysis patients. 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] has been shown to modulate the immune function of monocytes and macrophages. Patients with end-stage renal disease (ESRD) on chronic hemodialysis treatment usually present a deficiency of this active form of vitamin D 3 . The aim of this study was to investigate the effect of 1,25(OH) 2 D 3 replacement therapy on phagocytosis, bactericidal capacity, and oxidative metabolism of peripheral blood polymorphonuclear leukocytes (PMNL) and monocytes (MN) in chronic hemodialysis patients. Phagocyte function tests were performed before and after four weeks of an oral replacement therapy with 0.5 µg/day of 1,25(OH) 2 D 3 (Rocaltrol®). The superoxide (O 2 - ) generation of monocytes, measured by cytochrome c reduction and lucigenin-enhanced chemiluminescence (CL) from patients receiving hemodialysis treatment was significantly diminished compared to healthy controls. After the replacement therapy with 1,25(OH) 2 D 3 the O 2 - production showed a significant improvement, resulting in an increased cytochrome c reduction and lucigenin-CL response. The bactericidal capacity of MN was also impaired and exhibited a significant enhancement of their killing activity after the administration of 1,25(OH) 2 D 3 . On the other hand, the luminol-enhanced CL, which reflects the myeloperoxidase-dependent oxidative metabolism, and the phagocytic ability of MN was not affected by the hormone. The function of polymorphonuclear leukocytes (PMNL) from hemodialysis patients showed no impairment in the state of 1,25(OH) 2 D 3 deficiency and the replacement of the hormone did not enhance their function. These results suggest that the deficiency of 1,25(OH) 2 D 3 in patients with ESRD on chronic hemodialysis treatment may be responsible for an impaired monocyte function, which could be improved by an in vivo replacement of the hormone.

A 39-year-old man with pulmonary disease due to Mycobacterium xenopi is described. He had received prednisone and azathioprine for 5 years and prednisone in combination with cyclosporin A for 1 year in an effort to prevent rejection of his renal transplant. Shortly after the renal allograft was removed because of chronic rejection, the patient developed dyspnea and a decrease in vitality. He had no history of preexisting lung disease. A chest roentgenogram showed multiple nodular infiltrates in both lungs. M. xenopi was cultured from three sputum samples. The organism was susceptible to isoniazid, streptomycin, ethambutol, rifampin, pyrazinamide, and ethionamide. The patient was treated successfully with isoniazid, ethambutol, and rifampin for 3 months and with isoniazid in combination with rifampin for an additional 9 months, while he was maintained on continuous ambulatory peritoneal dialysis (CAPD). The literature on mycobacterial disease, especially in renal transplant recipients and patients on CAPD, is reviewed.