Dabrafenib plus trametinib in unselected advanced BRAF V600-mut melanoma: a non-interventional, multicenter, prospective trial.

OBJECTIVE: The efficacy of combined BRAF and MEK inhibition for BRAF V600-mutant melanoma in a broad patient population, including subgroups excluded from phase 3 trials, remains unanswered. This noninterventional study (DATUM-NIS) assessed the real-world efficacy, safety and tolerability of dabrafenib plus trametinib in Austrian patients with unresectable/metastatic melanoma. METHODS: This multicenter, open-label, non-interventional, post-approval, observational study investigated the effectiveness of dabrafenib plus trametinib prescribed in day-to-day clinical practice to patients ( N  = 79) with BRAF V600-mutant unresectable/metastatic melanoma with M1c disease (American Joint Committee on Cancer staging manual version 7), ECOG > 1, and elevated serum lactate dehydrogenase (LDH). The primary endpoint was 6-, 12- and 18-month progression-free survival (PFS) rates. Secondary endpoints were median PFS, disease control rate and overall survival (OS). RESULTS: The 6-, 12- and 18-month PFS rates were 76%, 30.6% and 16.2%, respectively. Subgroup analysis showed a significant PFS benefit in the absence of lung metastasis. The median PFS and OS were 9.1 (95% CI, 7.1-10.3) months and 17.9 (95% CI, 12.7-27.8) months, respectively. The 12- and 24-month OS rates were 62.7% and 26.8%, respectively. Subgroup analyses showed significant OS benefits in the absence of bone or lung metastasis and the presence of other metastases (excluding bone, lung, brain, liver and lymph nodes). Furthermore, S100 and Eastern Cooperative Oncology Group performance status (ECOG PS) showed a significant impact on survival. No new safety signals were observed. CONCLUSION: Despite an unselected population of melanoma patients with higher M1c disease, ECOG PS > 1 and elevated LDH, this real-world study demonstrated comparable efficacy and safety with the pivotal phase 3 clinical trials for dabrafenib-trametinib.

Thermal Characterisation of Hybrid, Flip-Chip InP-Si DFB Lasers.

WA detailed thermal analysis of a hybrid, flip-chip InP-Si DFB laser is presented in this work. The lasers were experimentally tested at different operating temperatures, which allowed for deriving their thermal performance characteristics: the temperature dependence of threshold current, lasing slope, and output spectrum. Using these data, the laser thermal resistance was calculated (Rth = 75.9 K/W), which allows for predicting the laser temperature during operation. This metric is also used to validate the thermal finite element models of the laser. A sensitivity study of the laser temperature was performed using these models, and multiple routes for minimising both the laser thermal resistance and thermal coupling to the carrier die are presented. The most effective way of decreasing the laser temperature is the direct attachment of a heat sink on the laser top surface.

Prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking.

BACKGROUND: Melanocytic nevi have a complex evolution influenced by several endogenous and exogenous factors and are known risk factors for malignant melanoma. Interestingly, tobacco use seems to be inversely associated with melanoma risk. However, the association between tobacco use and nevi and lentigines has not yet been evaluated. METHODS: We investigated the prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking in a cohort of 59 smokers and 60 age- and sex-matched nonsmokers, using a questionnaire and performing a total body skin examination by experts. RESULTS: No significant differences were detected between smokers and nonsmokers in the numbers of nevi, atypical nevi, and lentigines in sun-exposed areas (p = 0.966, 0.326, and 0.241, respectively) and in non-sun-exposed areas (p = 0.095, 0.351, and 0.546, respectively). CONCLUSION: Our results revealed no significant differences in the prevalence of nevi, atypical nevi, and lentigines between smokers and nonsmokers in sun-exposed and non-sun-exposed areas.

Circulating Tumor DNA as a Marker for Treatment Response in Metastatic Melanoma Patients Using Next-Generation Sequencing-A Prospective Feasibility Study.

We prospectively performed a longitudinal analysis of circulating tumor DNA (ctDNA) from 149 plasma samples and CT scans in Stage III and IV metastatic melanoma patients (n = 20) treated with targeted agents or immunotherapy using two custom next-generation sequencing (NGS) Ion AmpliSeq™ HD panels including 60 and 81 amplicons in 18 genes, respectively. Concordance of matching cancer-associated mutations in tissue and plasma was 73.3%. Mutant allele frequency (MAF) levels showed a range from 0.04% to 28.7%, well detectable with NGS technologies utilizing single molecule tagging like the AmpliSeq™ HD workflow. Median followup time of the tissue and/or plasma positive cohort (n = 15) was 24.6 months and median progression-free survival (PFS) was 7.8 months. Higher MAF ≥ 1% at baseline was not significantly associated with a risk of progression (Odds Ratio = 0.15; p = 0.155). Although a trend could be seen, MAF levels did not differ significantly over time between patients with and without a PFS event (p = 0.745). Depending on the cell-free DNA amount, NGS achieved a sensitivity down to 0.1% MAF and allowed for parallel analysis of multiple mutations and previously unknown mutations. Our study indicates that NGS gene panels could be useful for monitoring disease burden during therapy with ctDNA in melanoma patients.

Intravitreal Steroid Treatment for Uveitis Associated with Dabrafenib and Trametinib for Metastatic Cutaneous Melanoma.

Purpose: To report a case of bilateral retinal inflammation under long-term therapy with dabrafenib/trametinib for metastatic cutaneous melanoma.Methods: Retrospective chart review.Results: A 59-year-old patient with metastatic cutaneous melanoma diagnosed in 2004 under treatment with dabrafenib/trametinib since 2014 presented to our department with intraretinal hemorrhage and extrafoveal macula edema on the right eye and optic disc swelling on the left eye. The patient did not report visual complaints. After cessation of dabrafenib/trametinib and subconjunctival and intravitreal corticosteroid injections, optic disc swelling on the left eye recovered after 6 months. The macula edema on the right eye was treated with one intravitreal anti-VEGF (vascular endothelial growth factor) injection after encroaching upon the fovea 10 months after initial presentation. The final visual acuity was 20/20 on both eyes.Conclusion: Even after years of treatment with low dose dabrafenib/trametinib, ocular toxicity can develop. Such cases can respond well to intravitreal corticosteroids.

Patients with BRAF-Mutant Advanced/Metastatic Melanoma: Original Research on the Treatment Reality in Germany and Austria in the Era of Choice.

INTRODUCTION: Cutaneous melanoma is one of the most aggressive forms of skin neoplasms and represents a major cause of neoplastic or cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15% when the disease metastasizes to distant organs. The objective of our study was to evaluate the status quo of the current treatment standards in stage IV melanoma and rationale for therapy decisions in Germany and Austria between January 2016 and September 2018. METHODS: In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in the first, second, and third line with registered substances were analyzed using descriptive statistics. RESULTS: Ninety-nine patients (50.5% male) received a total of 172 treatment lines. The first (99 patients), second (56 patients), and third (17 patients) treatment lines were documented. Within the 80.8% of patients with stage IV melanoma, targeted therapy (TT) was more frequently administered as a first-line treatment than immunotherapy (IO) with checkpoint inhibitors (59.6% TT vs. 40.4% IO). Across all lines, patients received TT in 54.7% and IO in 43.0% of the cases. As targeted agents, dabrafenib plus trametinib was predominantly prescribed (72.3%), whereas the monotherapy with anti-programmed cell death protein 1 and anti-cytotoxic T lymphocyte-associated protein 4 antibodies or their combination was prescribed similarly often (50.0% vs. 47.3%). Most commonly, the treatment type was switched from TT to IO or vice versa upon disease progression. The most frequent rationales for prescribing either TT or IO were remission pressure (72.9%) or physician's preference (45.0%), respectively. Disease progression was a more frequent cause of treatment discontinuation than undesired events. CONCLUSION: Patients in Germany and Austria with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. TT was more frequently administered than IO while the rationale for prescribing a specific treatment type differed between the two.

Study of the effect of Sn grain boundaries on IMC morphology in solid state inter-diffusion soldering.

This paper reports on 3D phase field simulations of IMC growth in Co/Sn and Cu/Sn solder systems. In agreement with experimental micrographs, we obtain uniform growth of the CoSn3 phase in Co/Sn solder joints and a non-uniform wavy morphology for the Cu6Sn5 phase in Cu/Sn solder joints. Furthermore, simulations were performed to obtain an insight in the impact of Sn grain size, grain boundary versus bulk diffusion, IMC/Sn interface mobility and Sn grain boundary mobility on IMC morphology and growth kinetics. It is found that grain boundary diffusion in the IMC or Sn phase have a limited impact on the IMC evolution. A wavy IMC morphology is obtained in the simulations when the grain boundary mobility in the Sn phase is relatively large compared to the interface mobility for the IMC/Sn interface, while a uniform IMC morphology is obtained when the Sn grain boundary and IMC/Sn interface mobilities are comparable. For the wavy IMC morphology, a clear effect of the Sn grain size is observed, while for uniform IMC growth, the effect of the Sn grain size is negligible.

Associations between the use of specific psychotropic drugs and all-cause mortality among older adults in Germany: Results of the mortality follow-up of the German National Health Interview and Examination Survey 1998.

BACKGROUND: Use of psychotropic drugs is common among older adults. Population-based studies on the associations of psychotropic drug use with mortality are sparse. OBJECTIVES: To investigate the associations between the use of specific psychotropic drug groups (opioids, antipsychotics, antidepressants and benzodiazepines) and all-cause mortality among community-dwelling older adults in Germany. METHODS: Participants of the German National Health Interview and Examination Survey 1998 were followed up for mortality from 1997 to 2011. Persons aged 60-79 years with complete data on psychotropic drug use at baseline and on mortality follow-up were considered as study population (N = 1,563). Associations between the use of opioids, antipsychotics, antidepressants and benzodiazepines and all-cause mortality were examined by Cox proportional hazards models adjusted for sociodemographics (sex, age, community size, region, socioeconomic status), life style (smoking, sports, risky alcohol drinking) and health conditions (obesity, disability, history of cardiovascular diseases, diabetes, hyperlipidemia, hypertension, any cancers, any mental disorders) at baseline. RESULTS: After a median follow-up of 11.4 years, 21, 18, 23 and 26 deaths were documented among those who used at baseline opioids (n = 39), antipsychotics (n = 30), antidepressants (n = 53) and benzodiazepines (n = 54) with an unadjusted mortality rate (MR) of 57.7, 59.1, 44.6 and 53.7 per 1000 person-years, respectively. Meanwhile, 400 deaths were documented among 1,406 nonusers of any of the above mentioned psychotropic drugs with a MR of 26.7 per 1000 person-years. The age and sex adjusted mortality rate ratios in comparison with nonusers were 2.20 (95% confidence intervals 1.42-3.41), 1.66(1.03-2.70), 1.56(1.06-2.28), and 1.57(1.07-2.31) for the use of opioids, antipsychotics, antidepressants and benzodiazepines, respectively. In the fully adjusted Cox models, use of opioids (hazardous ratio 2.04, 95% confidence intervals 1.07-3.89), antipsychotics (2.15, 1.11-4.15) and benzodiazepines (1.76, 1.09-2.82), but not antidepressants, were significantly associated with an increased risk of mortality. CONCLUSIONS: Use of opioids, antipsychotics, benzodiazepines is significantly associated with an increased risk of all-cause mortality among community-dwelling older adults in Germany. Clinicians should be careful in prescribing these psychotropic drugs to older adults while patients already under psychotropic therapy should well balance the risks and benefits of drug use. Further studies with a larger sample size and information on specific indications for psychotropic drug use and mental comorbidities are required to confirm the findings of the present study.

Novel technology for microlenses for imaging applications.

Microlenses are an important functional element of a modern imaging device. Typically, they are fabricated from organic materials on top of individual pixels. Though they are widely used, they do exhibit a number of limitations. These are, but not limited to, thermal stability, radiation sensitivity, outgassing properties, additional topography, and difficulty in manufacturing asymmetrical, noncircular microlens designs using conventional manufacturing techniques. In this paper, we present a novel approach for the fabrication of microlenses. We report on the design, manufacturing, and characterization of microlenses fabricated from classical dielectric materials used in the manufacturing of CMOS semiconductor devices. These microlenses rely on a Fresnel optical design, provide functionality similar to the classical microlenses, and do not suffer from their limitations. We subjected these microlenses to several environmental reliability stress conditions, including pressure, temperature, humidity, and their variation. Moreover, we test their sensitivity to gamma rays and protons.

Body mass index may predict the response to ipilimumab in metastatic melanoma: An observational multi-centre study.

INTRODUCTION: Immunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects. METHODS: In this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI≥25). RESULTS: 40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, χ2), and lower likelihood of brain metastases (p = 0.012, χ2). No differences were found between both groups with respect to gender (p = 0.324, χ2), T-stage (p = 0.197, χ2), or the occurrence of side effects (p = 0.646, χ2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank). CONCLUSIONS: The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.

MiR221 promotes precursor B-cell retention in the bone marrow by amplifying the PI3K-signaling pathway in mice.

Hematopoietic stem cells and lineage-uncommitted progenitors are able to home to the bone marrow upon transplantation and reconstitute the host with hematopoietic progeny. Expression of miR221 in B-lineage committed preBI-cells induces their capacity to home to the bone marrow. However, the molecular mechanisms underlying miR221-controlled bone marrow homing and retention remain poorly understood. Here, we demonstrate, that miR221 regulates bone marrow retention of such B-cell precursors by targeting PTEN, thus enhancing PI3K signaling in response to the chemokine CXCL12. MiR221-enhanced PI3K signaling leads to increased expression of the anti-apoptotic protein Bcl2 and VLA4 integrin-mediated adhesion to VCAM1 in response to CXCL12 in vitro. Ablation of elevated PI3K activity abolishes the retention of miR221 expressing preBI-cells in the bone marrow. These results suggest that amplification of PI3K signaling by miR221 could be a general mechanism for bone marrow residence, shared by miR221-expressing hematopoietic cells.

Treatment of Primary and Metastatic Multifocal Mucosal Melanoma of the Oral Cavity with Imatinib.

BACKGROUND: Mucosal melanoma of the oral cavity is a rare entity and accounts for less than 1-3% of all melanomas. Contrary to cutaneous melanoma, primary oral melanoma more commonly harbors mutations in c-KIT. METHODS: A 64-year-old man presented with asymptomatic, multiple, brown-to-black macules in the oral cavity. A biopsy was taken and histopathology exhibited mucosal melanoma. In molecular analysis, a c-KIT mutation was proven and a CT scan revealed pulmonary metastases. Due to the multifocality of the lesions, the metastases, and the mutation status, a therapy with imatinib was initiated. RESULTS: After 1 year of therapy, progressive disease in the lung was noticed. Therefore, the therapy was switched to a PD-1 antagonist and a CTL-4 antibody. CONCLUSIONS: Our case suggests that imatinib may be considered as first-line treatment for both locally advanced and distant primary multifocal oral melanoma, for which surgery or radiotherapy of the primary tumor is impossible.

Association of psychotropic drug use with falls among older adults in Germany. Results of the German Health Interview and Examination Survey for Adults 2008-2011 (DEGS1).

PURPOSE: To investigate the association of psychotropic drug use with falls among older adults in Germany based on data from the National Health Interview and Examination Survey for Adults 2008-2011 (DEGS1). METHODS: DEGS1 collected data on drug use in the past 7 days and on falls occurred in the last 12 months. Study participants were older adults aged 65-79 years with complete data on drug use and falls (N = 1,833). Odds ratio (OR) and 95% confidence intervals (95% CI) were derived from logistic regression models adjusting for potential confounders including socio-demographic characteristics, health-related behaviors (alcohol drinking), body mass index and health conditions (frailty, vision impairment, disability, polypharmacy, blood pressure) as well as use of potential falls-risk-increasing drugs. SPSS complex sample methods were used for statistical analysis. RESULTS: Compared to people without falls, people with falls (n = 370) had a higher psychotropic drug use (33.1% vs. 20.7%, p < .001). After adjusting for potential confounders, use of psychotropic drugs overall was associated with a higher risk of falls (OR 1.64, 95% CI 1.14-2.37). This was particularly true for the use of synthetic psychotropic drugs (1.57, 1.08-2.28), antidepressants overall (2.88, 1.63-5.09) or synthetic antidepressants (2.66, 1.50-4.73), specifically, selective serotonin reuptake inhibitors (SSRIs) (6.22, 2.28-17.0). Similar results were found for recurrent falls. CONCLUSIONS: Use of psychotropic drugs overall, especially synthetic antidepressants like SSRIs, is associated with higher risks of falls and recurrent falls among community dwelling older adults aged 65-79 years in Germany.

Changes in prevalence of psychotropic drug use and alcohol consumption among the elderly in Germany: results of two National Health Interview and Examination Surveys 1997-99 and 2008-11.

BACKGROUND: Psychotropic drug use and alcohol consumption among older adults need to be monitored over time as their use or combined use bears risks of harms. Representative data on changes in prevalence, patterns and co-relates of substance use are lacking in Germany. METHODS: Participants were older adults (60-79 years) from two German National Health Surveys: 1997-99 (GNHIES98, N = 1,606) and 2008-11 (DEGS1, N = 2,501). Included were drugs acting on the nervous system used during the last 7 days. Alcohol consumption was measured by frequency (daily drinking) and quantity (risky drinking: ≥20/10 g/day alcohol for men/women). Changes in prevalence adjusted for potential socio-economic and health-related confounders were calculated by logistic regression models approximated by the SAS LSMEANS statement. RESULTS: The prevalence of overall psychotropic drug use (20.5% vs. 21.4%) remained constant between the two surveys. Significant changes were observed in the use of some psychotropics (all GNHIES98 vs. DEGS1): Synthetic antidepressants (3.9% vs. 6.9%), St. John's wort (2.9% vs. 1.1%), benzodiazepines (3.7% vs. 2.5%), benzodiazepine related drugs (0.2% vs. 0.8%), narcotic analgesics (3.0% vs. 4.1%), anti-dementia drugs (2.2% vs. 4.2%) and anti-epileptics (1.0% vs. 2.3%). Significant changes were also observed in long-term use of synthetic anti-depressants (3.2% vs. 5.9%), St. John's wort (2.0% vs. 0.6%) and opioid analgesics (1.0% vs. 2.2%). Further, we found significant changes in benzodiazepines use (3.3% vs. 1.4%) among men, opioids use (2.9% vs. 7.3%) among people with a lower social status, and overall psychotropics (26.8% vs. 32.5%) as well as opioids use (4.4% vs. 8.1%) among those with a worse health status. Moderate alcohol consumption increased significantly (58.0% vs. 66.9%). Risky drinking remained unchanged (16.6% vs. 17.0%). In spite of significant increases in daily alcohol drinking (13.2% vs. 18.4%) psychotropic drug use combined with daily drinking remained unchanged (1.8% vs. 2.7%). CONCLUSIONS: Although prevalence of overall psychotropic drug use remained stable, changes in the use of some psychotropic drug groups and alcohol consumption patterns have been observed. Further studies are required to investigate resulting health consequences and public health relevance of those outcomes.

IL-7 and immobilized Kit-ligand stimulate serum- and stromal cell-free cultures of precursor B-cell lines and clones.

Long-term proliferating, DH JH -rearranged mouse precursor B-cell lines have previously been established in serum- and IL-7-containing media from fetal liver, but not from bone marrow. Serum and stromal cells expose these pre-B cells to undefined factors, hampering accurate analyses of ligand-dependent signaling, which controls pre-B cell proliferation, survival, residence and migration. Here, we describe a novel serum-free, stromal cell-free culture system, which allows us to establish and maintain pre-B cells not only from fetal liver, but also from bone marrow with practically identical efficiencies in proliferation, cloning and differentiation. Surprisingly, recombinant kit-ligand, also called stem cell factor, produced as a kit-ligand-Fc fusion protein, suffices to replace stromal cells and serum, provided that it is presented to cultured pre-B cells in an optimal density in plate-bound, insolubilized, potentially crosslinking form. Additional recombinant CXCL12 and fibronectin have a minor influence on the establishment and maintenance of pre-B cell lines and clones from fetal liver, but are necessary to establish such cell lines from bone marrow.

Diabetes Surveillance in Germany - Background, concept and prospects.

Diabetes mellitus is a chronic disease that is associated with serious health problems and high costs. According to estimates gained from nationally representative health surveys conducted by the Robert Koch Institute (RKI), 4.6 million adults aged 18 to 79 suffer from diabetes in Germany. In addition, around 1.3 million adults have undetected diabetes. A surveillance system is currently being established at the RKI in order to gather the data sources available on diabetes in Germany and to provide reliable and comparable findings on time trends covering the frequency, progress of treatment, prevention and care of the disease. Next to identifying trends, diabetes surveillance also needs to detect differences in epidemiology that are related to social status or geographic region. Diabetes surveillance at the RKI is being undertaken in close cooperation with stakeholders involved in science, health-care provision, health policy and health-system self-governance. Furthermore, its progress is accompanied by an interdisciplinary scientific advisory board. Diabetes surveillance involves the following key elements: 1) the development of a research-based conceptual framework that uses indicators to appropriately measure developments in the disease; 2) the establishment of standards for the use of existing data sources and the identification of barriers to data usage and gaps in the data; and 3) the implementation of focused health reporting that is geared towards the target group. In addition to policy consultations, diabetes surveillance must guarantee the provision of timely and continuous information to the public together with the Federal Agency for Health Education. The implementation of a diabetes surveillance in Germany should act as a model and serve as a basis with which to establish the surveillance of other non-communicable diseases. In principle, indicator-based diabetes monitoring at the population level can be viewed as providing the body for evidence-based policy consultation and focused health policy. In turn, this should enable the implementation of effective disease prevention measures and high-quality care for all groups within the population.

Psychotropic drug use and alcohol consumption among older adults in Germany: results of the German Health Interview and Examination Survey for Adults 2008-2011.

OBJECTIVES: The use and combined use of psychotropic drugs and alcohol among older adults is a growing public health concern and should be constantly monitored. Relevant studies are scarce in Germany. Using data of the most recent national health survey, we analyse prevalence and correlates of psychotropic drug and alcohol use among this population. METHODS: Study participants were people aged 60-79 years (N=2508) of the German Health Interview and Examination Survey for Adults 2008-2011. Medicines used during the last 7 days were documented. Psychotropic drugs were defined as medicines acting on the nervous system (ATC code N00) excluding anaesthetics (N01), analgesics/antipyretics (N02B), but including opiate codeines used as antitussives (R05D). Alcohol consumption in the preceding 12 months was measured by frequency (drinking any alcohol-containing beverages at least once a week/a day) and quantity (alcohol consumed in grams/day; cut-offs: 10/20 g/day for women/men defining moderate and risky drinking). SPSS complex sample module was used for analysis. RESULTS: 21.4% of study participants use psychotropic medications, 66.9% consume alcohol moderately and 17.0% riskily, 51.0% drink alcohol at least once a week and 18.4% daily, 2.8% use psychotropic drugs combined with daily alcohol drinking. Among psychotropic drug users, 62.7% consume alcohol moderately, 14.2% riskily. The most frequently used psychotropic medications are antidepressants (7.9%) and antidementia (4.2%). Factors associated with a higher rate of psychotropic drug use are female sex, worse health status, certified disability and polypharmacy. Risky alcohol consumption is positively associated with male sex, smoking, upper social class, better health status, having no disability and not living alone. CONCLUSIONS: Despite the high risk of synergetic effects of psychotropic drugs and alcohol, a substantial part of older psychotropic drug users consume alcohol riskily and daily. Health professionals should talk about the additional health risks of alcohol consumption when prescribing psychotropic drugs to older adults.

Tumor-associated B cells in cutaneous primary melanoma and improved clinical outcome.

B cells often infiltrate the microenvironment of human tumors. B cells can both positively and negatively regulate antitumor immune responses. In several human cancers, higher numbers of CD20(+) TAB are associated with a favorable prognosis, whereas in human primary melanomas, this association is contentious. In this study, we determined the association of TAB numbers in cutaneous primary melanoma tissue samples and patients' overall survival. The CD20 immunohistochemistry on archival nonmetastasized and metastasized cutaneous primary melanoma tissues from 2 independent patient cohorts was performed. One cohort was used in class comparison for metastasis, the most important prognostic factor for overall survival, and the other cohort for a subsequent survival analysis. Survival association was further validated with RNA data from a third independent cohort. Whole tissue sections were read automatically via quantitative digital imaging and analysis. Survival data were analyzed by Cox proportional hazard modeling. We discovered that cutaneous primary melanomas without metastasis contain significantly more TAB than primary melanomas that had metastasized. At time of first diagnosis, a higher number of TAB is associated with a significantly better overall survival in patients with cutaneous primary melanomas of >1 mm Breslow depth. Also, higher CD20/CD19 tumor mRNA levels are correlated with a significantly better overall survival. Thus, our data support TAB numbers as a prognostic biomarker in cutaneous primary melanoma patients with a tumor of >1 mm Breslow depth. For a survey in larger studies, whole tissue section analysis seems to be key to accurate assessment of TAB numbers.