Miracle-dz/UniFAR-FTUs huggingface dataset:
Multiple myeloma – current status and future directions

Introduction: Multiple myeloma (MM) is a largely incurable plasma cell-derived cancer which requires treatment once clinical symptoms arise. Several ‘novel drugs' (proteasome inhibitors, immunomodulators) have been introduced during the last decade resulting in an improved prognosis. To maximize response quality and duration, multi-drug combinations, alternating sequences and low-dose ‘continuous' treatments are currently used. Among patients with MM relapse, those with extramedullary disease (EMD) are particularly challenging when it comes to treatment. Hopefully, genomic studies will in the future help to understand the clonal back and forth of MM tumors. This may ultimately result in the development of more ‘targeted' drugs. As of yet, only 4% of MM patients harbouring the BRAF V600E mutation feature a ‘druggable' genetic target. Areas covered: We review current treatment options, their limitations in particular settings and potential future approaches. We performed a literature review and queried the PubMed database including abstracts from recent congresses. Search terms: ‘multiple myeloma', ‘proteasome inhibitors', ‘immunomodulatory drugs', ‘stem cell transplantation' and drug-related terms. Expert opinion: First-line treatment in younger, medically fit subjects should consist of induction, consolidation and maintenance elements to maximize response. Unfortunately, ‘personalized' approaches are far behind us as druggable genetic changes yet need to be identified.
Paternal Heredity and Housing Characteristics Affect Childhood Asthma and Allergy Morbidity

ABSTRACT A birth cohort was initiated when each pregnant woman was asked for her own and her husband's history of asthma and allergic diseases at the time of recruitment. They were further inquired to verify their housing conditions, and current health status of children 3 to 5 years old at the time of interview. Paternal history was the most significant risk factor associated with reporting childhood morbidities at age of 3 to 5 years. Housing characteristics became meaningful variables only if the fathers were asthmatic or atopic. A 9-fold increase of risk was found if children with paternal history and also exposed to incense burning and water damage at home. This is the first epidemiological evidence of East Asia suggesting paternal heredity, with concurrent indoor hazardous exposures, as a predominant risk on developing childhood asthma and allergy.
Adult protection: The processes and outcomes of adult protection referrals in two English local authorities

• Summary: This article examines the processes and outcomes of adult protection referrals in two local authorities in England using adult protection monitoring data collected between 1998 and 2005, identifying learning for the use and development of adult protection monitoring. • Findings: Associations were found between aspects of process and outcome in adult protection case management; police and regulatory agency involvement increased over time, over four-fifths of referrals resulted in investigations which were associated with higher levels of inter-agency involvement, abuse was confirmed for over two-fifths of referrals, there was significant territorial variation across a range of process and outcome measures and specialist adult protection coordinators were associated with higher levels of monitoring and post-abuse work. The study concluded that more work is needed to improve and standardize adult protection monitoring data if it is to more effectively inform case management and inter-authority comparisons. • Applications: The evidence from the study suggests that adult protection monitoring data can be used to help review and organize adult protection work at agency, team and case levels and is consequently of potential value to team managers, social workers and specialist co-ordinators working in adult protection.
Evaluation of prediagnostic prostate‐specific antigen dynamics as predictors of death from prostate cancer in patients treated conservatively

Prostate‐specific antigen (PSA) dynamics have been proposed to predict outcome in men with prostate cancer. We assessed the value of PSA velocity (PSAV) and PSA doubling time (PSADT) for predicting prostate cancer‐specific mortality (PCSM) in men with clinically localized prostate cancer undergoing conservative management or early hormonal therapy. From 1990 to 1996, 2,333 patients were identified, of whom 594 had two or more PSA values before diagnosis. We examined 12 definitions for PSADT and 10 for PSAV. Because each definition required PSA measurements at particular intervals, the number of patients eligible for each definition varied from 40 to 594 and number of events from 10 to 119. Four PSAV definitions, but no PSADT, were significantly associated with PCSM after adjustment for PSA in multivariable Cox proportional hazards regression. All four could be calculated only for a proportion of events, and the enhancements in predictive accuracy associated with PSAV had very wide confidence intervals. There was no clear benefit of PSAV in men with low PSA and Gleason grade 6 or less. Although evidence that certain PSAV definitions help to predict PCSM in the cohort exist, the value of incorporating PSAV in predictive models to assist in determining eligibility for conservative management is, at best, uncertain.
Involvement of Chromosome 8 in Müllerian Adenosarcoma

Müllerian adenosarcoma (MA) is an uncommon biphasic neoplasm of the female genital tract, composed of malignant stroma and benign epithelium. Little is known about the molecular and cytogenetic aberrations in MA pathogenesis, including those with progression to sarcomatous overgrowth (SO). Herein, we report all cases of MA in which karyotyping was attempted at our institution. Twenty-one samples from 20 subjects consisted of 15 primary (7 without SO, 8 with SO) and 6 metastatic MA, were cytogenetically investigated in our institution. Karyotypes were successfully obtained in 14/21 (67%) cases and 9 (45%) had cytogenetic aberrations. Two (1 MA with SO and 1 metastatic MA) were markedly complex, displaying extreme aneuploidy with numerous rearrangements. Seven (2 MA without SO, 3 MA with SO, and 2 metastatic MA) demonstrated noncomplex clonal aberrations, of which 5 (71%) included an abnormality involving chromosome 8. Two tumors had rearrangements at 8q13 and another 3 tumors had extra copies of chromosome 8. In 5 cases, a normal karyotype (46,XX) was obtained (2 MA without SO, 2 MA with SO, and 1 metastatic MA). Further study is warranted to explore the genetic mechanism by which chromosome abnormalities, particularly those at 8q13, contribute to MA tumorigenesis.
Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2‐like tumor‐associated macrophages expressing the novel CD20 homolog MS4A8A

Tumor‐associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE‐1+ M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow‐derived macrophages (BMDMs) by combining M2 mediators (IL‐4, glucocorticoids) and tumor‐conditioned media (TCM). Admixture of MS4A8A+ TCM/IL‐4/GC‐treated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage‐like cells displayed a special gene signature. Admixture of these MS4A8A+ Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF‐κB activation and of the MAPK JNK and ERK did not show relevant effects, the p38α/β MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A+ TAM may serve as a novel cellular target for selective cancer therapy.
Overexpression of eIF5A‐2 is an adverse prognostic marker of survival in stage I non–small cell lung cancer patients

We have previously isolated an oncogene EIF5A2 (eukaryotic initiation factor 5A2) from a frequently amplified region at 3q of a primary ovarian cancer cell line, and demonstrated its impact on prognosis in human ovarian cancer. Amplification of chromosome 3q has also been detected frequently in non–small cell lung cancer (NSCLC), however, abnormalities of EIF5A2 and its clinicopathologic significance in NSCLC haven't been studied. In our study, the methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of EIF5A2 in 248 surgically resected NSCLCs (learning cohort) and another validation cohort of 120 stage I NSCLC patients. Overexpression and amplification of EIF5A2 was detected informatively in 48.7% and 13.7% of NSCLCs in learning cohort, 33.3% and 6.0% of NSCLCs in validation cohort. Overexpression of eIF5A‐2 was found to correlate with gene amplification, increased cell proliferation and advanced T stage. In learning cohort, eIF5A‐2 expression was evaluated as a strong prognostic factor on disease‐specific survival, but in subgroup analyses, it only retained its stratified significance in stage I set (Hazards ratio = 2.799, p = 0.001). In validation cohort, the impact of eIF5A‐2 expression on survival in stage I NSCLC patients was also observed (Hazard ratio = 2.097, p = 0.014). Our findings suggested that overexpression of eIF5A‐2 correlates with local invasion of NSCLC, and might serve as an adverse prognostic marker of survival for stage I NSCLC patients.
Pulmonary Rehabilitation in Neuromuscular Disorders

Respiratory failure is the most common cause of death in patients with severe myopathies, kyphoscoliosis, and anterior horn cell disorders. Duchenne muscular dystrophy (DMD) has an incidence of 1 in 3000 males, and, if left untreated, 55% to 90% of these patients will eventually die from ventilatory failure. However, only 36% of Muscular Dystrophy Association (MDA) clinic directors ever discuss or offer respiratory aids to their patients with chronic alveolar hypoventilation (CAH). Many principles of pulmonary rehabilitation that will be discussed in this article also appear to be infrequently applied. Thus, most patients with progressive CAH are untreated until they develop pneumonia, are hospitalized in acute respiratory failure, or have cardiopulmonary arrest. This is unfortunate because optimal management can both prolong the duration and the quality of life for patients with respiratory complications from neuromuscular disorders. Newly available management options for these patients with which the clinician can reach these goals will be discussed.
Microcystic, Elongated, and Fragmented Pattern Invasion in Ovarian Endometrioid Carcinoma.

To the Editor: We appreciate the interest in our article on microcystic, elongated, and fragmented (MELF) pattern invasion in ovarian endometrioid carcinoma, but respectfully disagree with the characterization in the above letter to the editor (1). Prior research on MELF pattern invasion in uterine endometrioid carcinoma (2), encouraged us to search for the finding in the ovary. As others have published, MELF invasion can be a focal finding (3) and we considered cases with any MELF invasion as positive for MELF invasion. Further, MELF pattern invasion is not part of the staging criteria and so may go unnoticed unless specifically sought out, as with our extensive retrospective review. MELF pattern invasion is a relatively new concept, first published in 2003 (2), therefore pathologists would not have even commented on it before that time. Given this, our findings of MELF pattern invasion in 45% of cases of ovarian endometrioid carcinoma is not surprising. MELF pattern invasion in ovarian endometrioid carcinoma may prove to have a wide range of prevalence, similar to MELF pattern invasion in uterine endometrioid carcinoma, which has a published prevalence ranging from 9% (4) to 44% (2). We further respectfully disagree on the opinion that our image does not depict MELF pattern invasion. Not only do we see the fragmented neoplastic glands lined by a flattened epithelium in a fibromyxoid stroma that are the definition of MELF pattern invasion (2), our images are morphologically similar to those published in several other articles on uterine MELF pattern invasion (3,5,6). Finally, we were also interested in the connection between MELF pattern invasion ovarian endometrioid carcinoma and cases with focal clear cell features. The cases with focal clear cell features did not meet the classification criteria for mixed ovarian carcinoma of endometrioid and clear cell type, but were ovarian endometrioid carcinoma with foci of cells with abundant cleared cytoplasm and large, hobnail nuclei with prominent nucleoli and endometrioid architecture throughout. The fact that these cytologic features are seen only in cases with MELF pattern invasion is notable, and, we believe, worthy of future study, particularly due to the possible association with Lynch Syndrome (7,8). We are grateful for the attention our research on MELF pattern invasion in ovarian endometrioid carcinoma has already received. We believe in the value of a thoughtful exchange of ideas as a way to advance the field of pathology and look forward to future discourse.
POPs’ effect on cardiometabolic and inflammatory profile in a sample of women with obesity and hypertension

Abstract Persistent organic pollutants (POPs) are man-made compounds with metabolic disruption impact. We investigated the effect of POP exposure in the cardiometabolic and inflammatory profile in a population of women with obesity and hypertension. In 43 premenopausal women (22 treated vs. 21 nontreated) undergoing bariatric surgery, blood and adipose tissue samples (visceral (vAT) and abdominal subcutaneous (scAT)) were collected. Median concentrations of ∑HCH and ∑POPs in vAT were significantly higher in treated women. VAT ∑HCH and scAT ∑HCH and ∑POPs concentrations were positively correlated with systolic blood pressure in the non-treated group. Our findings suggest that exposure to POPs and its accumulation in vAT and circulating in plasma may be associated to a higher cardiovascular risk in women with obesity and hypertension, with or without antihypertensive treatment.
Persistent human papillomavirus DNA is associated with local recurrence after radiotherapy of uterine cervical cancer

Human papillomavirus (HPV) DNA is considered as a hallmark of cervical cancer. We investigated whether persistent HPV DNA at the cervix is associated with local recurrence after radiotherapy in patients with locally advanced cervical cancer. A total of 156 patients with HPV‐positive cervical cancer (International Federation of Gynecology and Obstetrics stage IB–IVB) treated with radiotherapy between July 2003 and December 2006 were analyzed. HPV DNA was measured prior to radiotherapy and after completion of radiotherapy. The results of HPV DNA test at postradiotherapy 1, 3, 6 and 12 months were analyzed individually for association with local recurrence‐free survival (LRFS). In addition, the result of any last follow‐up HPV test within 24 months postradiotherapy was defined as the overall status of HPV at 24 months and was also analyzed for association with LRFS. HPV DNA was cleared in 127 patients (81.4%) and persistent in 29 patients (18.6%) by 24 months. In 18 patients with local recurrences, 14 patients (78%) showed positive HPV tests at 1–3 months. Among the various time points analyzed, a positive HPV test at 3 months was the most accurate predictor of local recurrence. Multivariate analysis indicated that overall status of HPV at 24 months, low HPV viral load and histologic grade as being significantly related to poor LRFS. In HPV‐positive cervical carcinoma treated primarily with radiotherapy, persistent HPV DNA within 24 months after treatment indicates a high risk of local recurrence. Diagnostic accuracy of HPV test was highest at 3 months.
Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor

Interleukin (IL)‐18 is a proinflammatory and immune‐enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL‐18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro‐IL‐18) in vitro. In addition, IL‐18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL‐18 is increased in EOC patients' sera at diagnosis as compared with age‐matched healthy women. IL‐18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL‐18 expression in cytokeratine‐positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL‐18. The detection of human IL‐18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL‐18 is tumor‐derived. However, IL‐18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL‐18 present in the ascitic fluid as pro‐IL‐18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL‐18 levels. Altogether these data indicate that IL‐18 in EOC fluids is predominantly tumor‐derived and that its lack of biological activity may represent a mechanism of tumor‐escape.
Histologically Bland “Extremely Well Differentiated” Thyroid Carcinomas Arising in Struma Ovarii can Recur and Metastasize

Struma ovarii (SO) infrequently harbor carcinomas that are histologically similar to those arising in the eutopic thyroid. We identified 10 such cases in our files. Eight patients presented with pelvic-related symptoms whereas 2 were incidentally discovered during pregnancy, all with disease confined to the ovary. There were 8 papillary thyroid carcinomas (PTCs) (2 classic and 6 follicular variant) and 2 poorly differentiated thyroid carcinomas. Two of the 10 thyroid carcinomas relapsed after an initial diagnosis of “benign” struma. Both occurred in young women with ovarian cysts discovered during pregnancy. The cystectomy from 1 patient showed thyroid follicles with nuclear features of the follicular variant of PTC whereas the cyst from the second patient showed thyroid follicles with subtle nuclear features, suggestive but not diagnostic of PTC. Both patients presented with disseminated PTC 3 and 4 years after the initial diagnosis, involving the pelvis in both cases and also the liver parenchyma in 1 case. The 2 patients received radioactive iodine therapy after thyroidectomy and are both alive with disease 6 years after diagnosis. The criteria separating hyperplastic nodules from well-differentiated follicular variant of PTC in the thyroid gland seem to be applicable to thyroid-type carcinomas arising in SO. The propensity for adverse clinical behavior does not seem to be related to the grade or histologic type of carcinoma in this small series. The hormonal milieu during pregnancy may lead to progression of malignant SO and such patients should be closely followed, particularly if their treatment consists of cystectomy alone.
A smoking‐based carcinogenesis model for lung cancer risk prediction

Lung cancer is the leading cancer killer for both men and women worldwide. Over 80% of lung cancers are attributed to smoking. In this analysis, the authors propose to use a two‐stage clonal expansion (TSCE) model to predict an individual's lung cancer risk based on gender and smoking history. The TSCE model is traditionally fitted to prospective cohort data. Here, the authors describe a new method that allows for the reconstruction of cohort data from the combination of risk factor data obtained from a case‐control study, and tabled incidence/mortality rate data, and discuss alternative approaches. The method is applied to fit a TSCE model based on smoking. The fitted model is validated against independent data from the control arm of a lung cancer chemoprevention trial, CARET, where it accurately predicted the number of lung cancer deaths observed.
Guideline on the Management of Hand Eczema ICD‐10 Code: L20. L23. L24. L25. L30

© Dt. Dermatologische Gesellschaft u. a. • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/Suppl 3 – S1–S15 JDDG | Supplement 3 2009 (Volume 7) 1 Preamble Hand eczema (HE), also known as hand dermatitis [note 1], is one of the most common diseases of the skin. Eczema of the hands is not a homogenous disease entity, but instead occurs in various forms, and comprehensive differential diagnosis is often necessary. The disease can range in severity from very mild to chronic severe disease that can even prevent the patient from working for extend ed periods of time and may be refractory to treatment. Chronic hand eczema is very costly and involves significant impairment of the quality of life of the patient. Several therapy options are avail able, but the treatment of chronic hand eczema is often difficult and unsatisfactory. Therapy is complex and requires multimodal management. Large, highquality, randomized controlled clinical studies on the effectiveness of even estab lished therapy options are lacking. The following guideline provides a starting point for an evidence-based approach to hand eczema, presenting the classification, diagnosis, prevention, therapy, and rehabilitation of this disease. Other relevant guidelines are also mentioned for further reference. 2 Objectives The diagnosis and treatment of hand eczema is difficult. Dermatologists in particular face a challenge, as affected patients usually seek the advice of a dermatologist who is then charged with performing appropriate testing and overseeing treatment. The goal of this guideline, which is primarily aimed at dermatologists, is to outline the classification, diagnosis, therapy, and advising of patients with hand eczema and to make recommendations for a standard ized approach to the disease (Figure 1). Guideline on the Management of Hand Eczema