Suppression of Rotational Domains of CuI Employing Sodium Halide Buffer Layers.

The occurrence of rotational domains is a well-known issue for copper iodide (CuI) that naturally occurs for growth on popular substrates like sapphire. However, this has detrimental effects on the thin film quality like increasing surface roughness or deteriorated transport characteristics due to grain boundary scattering. Utilizing pulsed laser deposition and the in situ growth of sodium chloride (NaCl) and sodium bromide (NaBr) template layers, studies were performed on their potential on suppressing the formation of rotational domains of CuI on c-plane sapphire and SrF2(111) substrates. Corresponding samples were investigated concerning their epitaxial properties and further characterized regarding (volume) crystalline, morphological, and electrical properties. Particularly for NaBr template layers, fully single-crystalline growth of CuI thin films was obtained and resulted in significantly reduced surface roughness of the CuI layer.

Pomalidomide, dexamethasone, and daratumumab immediately after lenalidomide-based treatment in patients with multiple myeloma: updated efficacy, safety, and health-related quality of life results from the phase 2 MM-014 trial.

Patients with relapsed/refractory multiple myeloma (RRMM) need proven subsequent therapies after early-line lenalidomide treatment failure. The phase 2 MM-014 trial (NCT01946477) investigated pomalidomide, dexamethasone, and daratumumab after 1 to 2 prior treatment lines (62.5%, 1 prior line) in patients with RRMM and prior lenalidomide (75.0%, lenalidomide refractory). With a median follow-up of 28.4 months, overall response rate was 77.7% (52.7% achieved very good partial response or better) and median progression-free survival was 30.8 months. For patients with lenalidomide-refractory disease, these outcomes were 76.2%, 47.6%, and 23.7 months, respectively. No new safety signals were observed; 64.3% experienced grade 3/4 neutropenia. Health-related quality of life was preserved or trended toward improvement through 12 treatment cycles. Pomalidomide, dexamethasone, and daratumumab given immediately after early-line lenalidomide-based treatment continues to demonstrate safety and efficacy, supporting pomalidomide-dexamethasone as a foundation of combination therapy in RRMM and providing evidence that the immunomodulatory agent class delivers benefit after lenalidomide treatment failure.

Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment.

Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1-21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.

Long-term outcomes, secondary malignancies and stem cell collection following bendamustine in patients with previously treated non-Hodgkin lymphoma.

Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Gender Wage Gap Accounting: The Role of Selection Bias.

Mulligan and Rubinstein (2008) (MR) argued that changing selection of working females on unobservable characteristics, from negative in the 1970s to positive in the 1990s, accounted for nearly the entire closing of the gender wage gap. We argue that their female wage equation estimates are inconsistent. Correcting this error substantially weakens the role of the rising selection bias (39 % versus 78 %) and strengthens the contribution of declining discrimination (42 % versus 7 %). Our findings resonate better with related literature. We also explain why our finding of positive selection in the 1970s provides additional support for MR's main hypothesis that an exogenous rise in the market value of unobservable characteristics contributed to the closing of the gender gap.

A case of seronegative catastrophic antiphospholipid antibody syndrome.

Catastrophic antiphospholipid antibody syndrome (CAPS) is a rare syndrome associated with multiorgan failure that carries a high mortality rate. It has been defined previously by the presence of autoantibodies in a patient with acute multiorgan failure as a result of small vessel occlusion by multiple thrombi. We report a patient who meets all criteria of CAPS except for persistent seronegativity.

Differentiation of pigmented Spitz nevi and Reed nevi by integration of dermatopathologic and dermatoscopic findings.

BACKGROUND: It is unclear whether pigmented Spitz and Reed nevi are distinct morphologic entities or part of the spectrum of Spitz nevi. METHODS: In a retrospective observational study we analyzed dermatopathologic slides of 22 cases with clinical and dermatoscopic features indicative of pigmented Spitz or Reed nevus in a blinded fashion according to predefined criteria and subsequently correlated dermatopathologic with clinical and dermatoscopic findings. RESULTS: We differentiated pigmented Spitz and Reed nevus dermatopathologically by their capacity of melanin production and a vertical versus horizontal growth pattern. Based on histopathology 20 nevi (91%) could be reliably diagnosed as Reed nevus (68%, n=15) or as pigmented Spitz nevus (23%, n=5). In two cases (9%, n=2) it was not possible to make a clear distinction from a dermatopathologic point of view. Dermatopathologic-dermatoscopic correlation showed that Reed nevi were characterized by a dermatoscopic pattern of peripheral radial lines or pseudopods (fascicular growth pattern), whereas pigmented Spitz nevi were typified by a pattern consisting of clods (nested growth pattern). "Spitz cells" (large epithelioid melanocytes) were more commonly found in Spitz nevi (100%, n = 5) but were also present in Reed nevi (n=6, 40%). Spindle cells were found in both types of nevi. CONCLUSIONS: Pigmented Spitz and Reed nevi can be reliably distinguished based on their dermatopathologic and dermatoscopic patterns. The specific dermatopathologic patterns of pigmented Spitz and Reed nevi correspond well to their dermatoscopic patterns. The presence of "Spitz cells" or spindle cells should not be regarded as the decisive criterion to differentiate between these two entities.

Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial.

PURPOSE: Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM. PATIENTS AND METHODS: In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m(2), with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone. RESULTS: An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients). CONCLUSION: Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.

Cutaneous and uterine leiomyomatosis and ovarian cystadenoma associated with deficiency of fumarate hydratase.

We report on an exceedingly rare case of cutaneous and uterine leiomyomatosis in a 58-year-old Caucasian woman associated with ovarian cystadenoma and complete deletion of the fumarate hydratase gene. All patients and their family members with verified mutation have to be regularly screened for associated neoplasms, in particular papillary renal cell carcinoma (HLRCC, hereditary leiomyomatosis and renal cell cancer).

Expanding spectrum of the association between Type 1 Gaucher disease and cancers: a series of patients with up to 3 sequential cancers of multiple types--correlation with genotype and phenotype.

In Gaucher disease (GD), inherited deficiency of lysosomal glucocerebrosidase due to mutations in GBA1 gene results in accumulation of glucosylceramide in tissue macrophages, systemic macrophage activation, and a complex multisystemic phenotype. We and others have reported an increased risk of multiple myeloma and other malignancies in non-neuronopathic Type 1 GD (GD1). Here, we describe a subset of GD1 patients with multiple malignancies. In our cohort of 403 patients with GD1, nine patients (2.2%) developed two or three different types of cancers either consecutively or simultaneously. Patients were characterized by age at diagnosis of GD1, GBA1 genotype, disease severity, age at cancer diagnosis, enzyme replacement therapy (ERT) status, and splenectomy status. Of the nine patients, six developed two types of malignancies and three had three cancers each. Overall, the hematologic malignancies comprised lymphoma/leukemia (4) and multiple myeloma (4). Nonhematologic malignancies included colon (2), lung (2), thyroid (2), and prostate cancer (1). Of the seven patients who received ERT, the first cancer was diagnosed before initiation of ERT in all but one. Asplenic patients were more likely to have single or multiple cancers compared with patients with intact spleens (P < 0.0072 and P < 0.0203, respectively). Our data strengthen the association of GD1 and cancer and suggest that patients may be at risk of developing multiple malignancies. We found an association between splenectomy and multiple cancers in GD1. It will be of interest to determine whether timely ERT and declining rates of splenectomy will translate into declining rates of multiple and single cancers.

Selection and validation of candidate housekeeping genes for studies of human keratinocytes--review and recommendations.

Gene expression analysis using real-time PCR has become an integral part of biomedical research. Appropriate data normalization based on stably expressed housekeeping genes is crucial for reliable results. Thus, candidate housekeeping genes require careful evaluation with regard to the individual experimental system before being selected for studies of human keratinocytes. Future research may be based on published data, as provided by Minner and Poumay in this issue.

Wavelength-dependent induction of CYP24A1-mRNA after UVB-triggered calcitriol synthesis in cultured human keratinocytes.

Earlier investigations in our laboratory have demonstrated that UVB irradiation of cultured human keratinocytes induces the conversion of 7-dehydrocholesterol (7-DHC) to hormonally active 1alpha,25-dihydroxyvitamin D3 (calcitriol). In the research presented here, we have investigated the influence of UVB-triggered calcitriol production on gene expression of the vitamin D3 hydroxylating enzymes catabolic 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), active vitamin-D3-25-hydroxylase (CYP27A1), and 25-hydroxyvitamin-D3-1alpha-hydroxylase (CYP27B1) using real-time PCR. Our results demonstrate a marked and wavelength-dependent induction of CYP24A1-mRNA in cultured human keratinocytes supplemented with 7-DHC, which parallels the spectral optimum at about 300 nm of calcitriol production as detected by HPLC and radioimmunoassay. Owing to the high sensitivity of real-time PCR, we provide evidence of a wavelength-dependent induction of CYP24A1-mRNA even in 7-DHC-deficient keratinocytes. Interestingly, we have found a strong but transient induction of CYP24A1-mRNA in non-irradiated keratinocytes, followed by accelerated cell proliferation. In contrast, UVB and calcitriol had no effect on gene expression of CYP27A1 and CYP27B1. We conclude from these experiments a constitutive gene expression of the vitamin D3 hydroxylases, whereas the catabolic enzyme CYP24A1 is markedly regulated by UVB, calcitriol, and perhaps cell proliferation. If confirmed at protein level, these findings could have an impact on epidermal vitamin D3 metabolism and its modulation by UVB in health and disease.

Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia.

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m2 on days 1-4 and rituximab 125, 250 or 375 mg/m2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.