Weill Medical College Research Articles

The 14th Spring Seminar of the Korean Pathologists Association of North America.

This Special Section is a compilation of the lectures on gastrointestinal and pancreaticobiliary pathology presented at the 14th annual spring seminar of the Korean Pathologists Association of North America (KOPANA). This seminar was held in conjunction with the 104th annual meeting of the United States and Canadian Academy of Pathology (USCAP) from March 19–21, 2015, in Boston, Massachusetts. There are 6 articles presented in this Special Section. The first by Ahn and Park presents recent updates in gastric pathology, including a definition of gastric preneoplastic lesions, various morphologic types of gastric adenocarcinomas, and important histopathologic features of endoscopic submucosal dissection specimens. In the second, Bae and colleagues describe 2 different morphologic patterns of multistep carcinogenesis with implications for 3 different molecular pathways of carcinogenesis in colorectal cancers (CRCs). This article aims to provide a better understanding of the differences in CRCs affecting different colonic sites with regard to age of onset, sex, race, and geographic area, thus further elucidating the different clinicopathologic features of CRCs in association with the proposed molecular carcinogenesis pathways. Next, Lee and colleagues address various clinical and surgical aspects of idiopathic inflammatory bowel disease (IBD) that are pertinent to practicing pathologists. Also, topics such as IBD in patients with primary sclerosing cholangitis and the current status of IBD in Asia are briefly reviewed. The article by Jang and Ahn introduces the concept of tumoral and flat intraepithelial neoplasia to describe various premalignant lesions of the pancreatobiliary region. This dichotomous concept is proposed to further understand the biologic behavior of premalignant lesions of pancreatobiliary tract, ampulla of Vater, and gallbladder. The article outlines the histopathologic spectrum of changes encountered in tumoral and flat intraepithelial neoplasia, reflecting on the inherent differences in the genetic profiles of these groups of premalignant lesions. In the fifth article, Kim and Hong put forth recent updates on neuroendocrine tumors of gastrointestinal and pancreatobiliary tracts in concordance with the updates in this category of tumors proposed in the 2010 World Health Organization classification scheme. In this review, they address issues dealing with grading and prognostic markers of the neuroendocrine tumors. Finally, Wang and Park present a brief history of successes and failures of targeted therapeutic strategies for gastrointestinal malignancies. They also present information about the next generation of clinical oncology trial designs. The next 10 years of precision medicine oncology trials, which are guided by genomic testing of tumors, are certainly deemed to bear a significant impact on the practice of surgical pathology as it exists today. Pathologists have to equip themselves with the requisite skills to effectively deal with new emerging roles and responsibilities in this era of precision medicine. KOPANA was founded in 1992 and by 2001 had a membership of more than 200 Korean pathologists practicing in North America in a variety of venues such as universities, community hospitals, private laboratories, and research institutes. Currently, about 50 American pathologists of Korean heritage (Korean American pathologists) are KOPANA members and their number is growing. Now is an important transition time for KOPANA, as considerable numbers of our older members have retired or are approaching retirement. Fifteen years ago, KOPANA began convening its spring seminar in conjunction with the annual meeting of USCAP to provide opportunities for networking, education, and enjoyment for our members. Our spring seminar has always been an excellent educational event for both our members and pathologists from Korea. Each year our invited speakers include not only our Korean American members but also pathologists in Korea. This has been a perfect venue for professional networking between pathologists in 2 geographic areas. The Korean Society of Pathologists (KSP) was founded in 1946 and currently has about 1100 members. The KSP mission is to provide pathologists with high-quality continuing medical education (CME). This is accomplished by supporting a broad range of CME programs including spring and fall annual meetings, 16 subspecialty study groups, and 4 regional societies. The Journal of Pathology and Translational Medicine (http://www.jpatholtm.org) is KSP’s peer-reviewed, international scientific journal that is focused on introducing and evaluating new knowledge and methodologies. KSP also Accepted for publication October 14, 2015. From the Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington (Dr Lee); the Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (Dr Yu); and the Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Weill Medical College of Cornell University, Houston, Texas (Dr Ro). The authors have no relevant financial interest in the products or companies described in this article. doi: 10.5858/arpa.2015-0381-ED Reprints: Jae Y. Ro, MD, PhD, Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin St, M227, Houston, TX 77030 (email: jaero@houstonmethodist.org).

HIV infection is associated with a lower rate of gestational weight gain and reduced neonatal length

BackgroundAdequate gestational weight gain (GWG) and neonatal growth are important, respectively, for favorable birth outcomes and survival of infants through the first year. In sub‐Saharan Africa, underlying infections, such as HIV, may adversely impact GWG and neonatal growth. We investigated trends in GWG among HIV‐infected and ‐uninfected women in northern Uganda; and, examined growth parameters of their HIV‐exposed and ‐unexposed neonates.Methods403 (133 HIV‐infected and on treatment vs. 270 ‐uninfected) pregnant women were recruited into this study from the antenatal clinic of Gulu Hospital. Women's height and weight were measured at enrollment (mean (±SD) gestational age =19.4 (±−3.8) weeks) and weight was measured at each follow‐up visit. After delivery, a subsample (n=246) of dyads was enrolled into a postnatal cohort. At one month postpartum, length and weight were measured and growth indicators (HAZ, WAZ and WHZ) were evaluated using the 2006 WHO standards. Other important variables were documented at recruitment using a detailed questionnaire. Multivariate regression models were employed to determine whether HIV status was associated with 1) the weekly rate of GWG and 2) neonatal indicators of growth.ResultsAdjusted models indicated a quadratic trend in GWG in both HIV infected and uninfected pregnant women. The rate of GWG among HIV infected women was significantly lower than that of HIV uninfected women (p=0.001). Prenatal HIV exposure was associated with significantly lower HAZ (p=0.013) and a nonsignicant trend towards lower WAZ; but, HIV exposure was not associated with WHZ at one month postpartum. HIV‐exposed neonates were more likely to be stunted (HAZ≤−2) than those who were –unexposed (adjusted odds ratio (aOR) (95%CI): 3.48 (1.29; 9.40).ConclusionThese results provide strong justifications for studies to understand mechanisms that underlay the negative effects of HIV infection or exposure on gestational weight gain and linear growth of HIV exposed neonates in this context.Support or Funding InformationThis research was funded in part by Cornell University Weill Medical College Intercampus Seed Funds, K01 MH098902 from NIMH and USAID Cooperative Agreement AIDOAAL1000006

Progression of antepartum depression differs by level of perceived social support and food insecurity

BackgroundAntepartum depression (AD) is a risk factor for adverse pregnancy outcomes and may be worsened by food insecurity (FI) and lack of social support (SS). We studied the progression of AD from mid gestation to term and examined whether such progression differed by measures of SS and longitudinal measures of FI.Methods403 women were recruited (mean (±SD) gestational age =19.4 (±−3.8) weeks) and followed to term or dropout. At baseline, SS was assessed using a modified Duke‐UNC functional scale. Women were binned into 2 SS groups, based on scoring < or ≥ than the median SS value. FI (IFIAS) and AD (CES‐D≥17) were assessed at each visit using validated scales. Other variables were assessed at baseline using structured tools. Separately by SS category, we used mixed effects logistic regression models to examine the progression of AD; and, assessed whether such AD progression differed by longitudinal measures of FI.ResultsAt baseline, 55.8% of the pregnant women belonged to the higher SS group. At this time point, the prevalence of AD among women in the low SS group (80.9%) was 2 times higher than similar levels in the higher SS group (40.4%). AD in the low SS group tended to decline with increasing gestational age but was always more prevalent than AD in the high SS group. In both SS groups, the progression of AD was positively associated with longitudinal measures of FI; and, the effect of FI on the progression of AD attained statistical significance among women in the low SS group. In the adjusted analyses, the probability of AD was three times higher among food insecure women in the low SS group than it was among food secure women in the high SS category.ConclusionsWe observed high levels of antepartum depression among women in northern Uganda that differed by social support and food insecurity suggesting the need for integrating mental health services that include food security and social support components into antenatal programs in this or similar contexts.Support or Funding InformationThis research was funded in part by Cornell University Weill Medical College Intercampus Seed Funds, K01 MH098902 from NIMH and USAID Cooperative Agreement AIDOAAL1000006

Effects of Anti-Glycoprotein Antibodies on Response of Immune Thrombocytopenia Patients to Thrombopoietin Receptor Agonists and on Megakaryocytes Viability

BackgroundImmune Thrombocytopenia (ITP) is a bleeding disorder due to a combination of increased platelet destruction and reduced production, often secondary to anti-platelet/megakaryocyte antibodies.The presence of antibodies to glycoproteins (GP) IIb/IIIa (integrin αIIbβ3) and GPIb/IX, detected in majority of ITP patients, may correspond to different responses to treatment, i.e., anti-GPIb is associated with more severe disease, and less responsive to intravenous immunoglobulins and steroids.Thrombopoietin Receptor Agonists (TPO-RA) increase platelet production by stimulation of megakaryopoesis. Predictors of response to TPO-RA and influence of antibody profile on response are currently unknown. In our previous study we investigated Absolute Immature Platelet Fraction (A-IPF) prior to TPO-RA treatment and did not find a correlation between A-IPF, anti-GP antibodies, and platelet counts.The aims of this study were to further investigate:1. The role of anti-GP antibodies in response to TPO-RA;2. Effect of patients' antibodies on megakaryocyte (MK) viability, maturation, apoptosis and formation of proplatelets (in vitro);3. The influence of patients' clinical characteristics on response to TPO-RA.Materials and Methods91 patients with persistent or chronic ITP, were treated at Weill Medical College of Cornell University until January 2015 with TPO-RAs: 52 patients received eltrombopag, 22 romiplostim and 17 avatrombopag. Serum samples of 84 patients were analyzed for the presence of anti-GP by MAIPA assay as previously described.Patients with baseline platelet counts less than <30x109/L were defined as responders to TPO-RA if the average of their six median monthly platelet counts was ≥50x109/L and doubled from average baseline counts (prior to TPO-RA). Patients with baseline platelet counts 30-50x109/L were responders if the average platelet count was ≥75x109/L.MKs were derived from human umbilical cord blood stem cells as previously described. Cells were grown using SFEM medium, adding on day 0 of culture 50 ng/ml recombinant TPO and aliquots of serum of ITP patients or healthy controls. The percentages of immature (CD41+/CD42-), mature (CD41+/CD42+), viable and apoptotic MKs were analyzed by flow cytometry on day 12. Apoptosis was analyzed by measuring Mitochondrial Outer Membane Potential (MOMP) and Phosphatidyl Serine (PS) externalization. MKs were considered apoptotic if they had positive staining for PS externalization, viable if positive for MOMP, and dead if positive for 7-Aminoactinomycin D (7AAD).Proplatelet formation by MKs was analyzed by microscopy.Statistical analysis using unpaired T-test and Pearson correlation test were performed.ResultsNinety-one patients were included, 40 male (44%) and 51 female (56%), with a median age of 37.4 years (range 2-87). Median duration of ITP before TPO-RA treatment was 8 years (range 0.3-45).The 18/91 (19.8%) non-responders to TPO-RA were not different from the 73/91 responders in age, gender, number of prior treatments, duration of ITP, and past splenectomy. The presence of either or both anti-GP antibodies was correlated with average lower platelet counts on TPO-RA: 82.3 x109/L versus 123x109/L in patients without detected antibodies ("neither") (p=0.003). However, the response to TPO-RA was not influenced by the type of antibody: in patients with anti-GPIb the average platelet count was 76.1x109/L, and with anti-GPIIb/IIIa 80.7x109/L (Figure 1). In culture, excess dead MKs were found in anti-GPIb group and antiGPIb&antiGPIIb/IIIa group compared to "neither" group (p=0.0013 and p=0.027 respectively) and comparing antiGPIb&antiGPIIb/IIIa to control (p=0.0025). We did not observe changes in the degree of MK apoptisis or in MK maturation in the presence of serum antibodies. In cultures treated with serum of patients having anti-GPIb, less proplatelets were detected comparing to control (p=0.044) or to "neither" (p=0.0039).We conclude that patients with anti-GP antibodies respond less to TPO-RA, however there is no difference in response to TPO-RA between patients having anti-GPIb and anti-GPIIb/IIIa, unlike responses to other treatment modalities (e.g., steroids or immunoglobulins). TPO-RA could be a preferable treatment option in ITP patients having anti-GPIb. [Display omitted] DisclosuresOff Label Use: Eltrombopag, romiplostim and avatrombopag are a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. In some preliminary studies these medicines found as safe and effective treatment option in children and adolescents. Bussel:amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Novartis: Consultancy, Research Funding; Genzyme: Consultancy; BiologicTx: Research Funding; Ligand: Consultancy, Research Funding; Eisai: Consultancy, Research Funding; Shionogi: Consultancy, Research Funding; momenta: Consultancy; Protalex: Consultancy; Symphogen: Consultancy.

Carfilzomib and Dexamethasone in untreated symptomatic multiple myeloma

Introduction: Treatment of refractory B cell malignancies with engineered T cells expressing chimeric antigen receptors (CARs) directed against CD19 has shown dramatic anti-tumor activity. CS1 (CD319) is a highly expressed surface glycoprotein on malignant plasma cells (mPCs) and promotes their adhesion to the bone marrow niche,making it a relevant target forCARtherapy inmultiplemyeloma (MM). The present work addresses the feasibility of CAR T cell generation fromMM patients after intense chemotherapy and an analysis of their therapeutic potential against primary mPCs. Materials and methods: We designed a CS1 specific CAR with an antigen-binding domain derived from the humanized monoclonal antibody elotuzumab (HuLuc63), comprising a signaling module of CD3 zeta and CD28. CS1 CAR gene constructs were lentivirally transferred to patient bulk CD4+ or CD8+ T cells. Results: We confirmed prevalently high CS1 antigen expression on mPCs in all patients. Absolute T cell counts in peripheral blood (PB) from pre-treated MM patients were lower compared to healthy donors, with predominant drop in CD4+ T cell counts. Max 50 ml of PB were sufficient for successful generation of CS1 CAR T cells in all (n 1⁄4 5) patients, and expansion to therapeutic doses within 2 weeks. In vitro functional testing of CAR T cells showed production of IL-2 and IFNg, proliferation in response to antigen recognition and specific lysis of MM cell lines. In a FACS based cytotoxicity assay, co-culture of mPCs with autologous or allogeneic CS1 CAR T cells resulted in rapid destruction of up to 90% of mPCs in 4 hours, whereas control T cells (untransduced and CD19 CAR T cells) had no effect. In a mouse xenograft myeloma model (NSG/MM1.S) patient-derived CS1 CAR T cells showed dramatic anti-myeloma activity, comparable to CS1 CAR T cells from healthy donors. As we observed CS1 expression also on lymphocyte subsets (B, T, NK) in MM patients, the potential ability of CS1 directed CAR T cell therapy to induce fratricide towards CS1+ lymphocytes remains a concern and is focus of ongoing research. Conclusion: Our data illustrate the preclinical feasibility to generate aCS1CARTcell productwith an excellent effector function against primarymPCs, requiring only small volumes of patients’ PB and clinically acceptable lead times. Determining the optimal setting for clinical translation however still warrants careful considerations with regards to possible induction regimens and supportive care. RS-003 Carfilzomib and Dexamethasone in untreated symptomatic multiple myeloma P. Forsberg, A. Rossi, R. Pearse, A. Perry, K. Pekle, D. Jayabalan, S. Ely, M. Coleman, R. Niesvizky, T.M. Mark Department of Medicine, Division of Hematology / Oncology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA; Department of Pathology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY, USA

CORR Insights(®): The Knee Society Short Form Reduces Respondent Burden in the Assessment of Patient-reported Outcomes.

P atient-reported outcome measures (PROMs) are particularly relevant in evaluating orthopaedic procedures like total joint arthroplasty because pain relief and functional improvement are key outcomes of this surgery [5]. The original Knee Society Score, which was published in 1989 and adopted widely in the orthopaedic community, clearly demonstrates the early recognition of the importance of PROMs in assessing the effectiveness of TKA [4]. The new Knee Society Knee Scoring System, which was developed in 2012, aimed at making the system more patientcentered by increasing the number of patient questions as well as enhancing its psychometric properties [6, 7]. The need for validated PROMs has grown substantially in recent years as a result of the increasing emphasis on patient-reported outcomes as measures of quality of care. Despite the strides made in this field, challenges in developing PROMs continue to revolve mainly around two issues: (1) Collecting all the necessary information without overburdening the patient, and (2) establishing the clinical meaningfulness of PROMs score. Considerable work has been done to address the former issue. Shorter forms of many PROMs have been created. Additionally, computeradaptive approaches, which can get more information from patients using fewer questions, have also been developed for some PROMs. Less work, however, has been done on the issue of clinical meaningfulness, which limits the translation of PROMs findings to clinical practice as hard endpoints and quality measures. The current paper by Scuderi et al. aimed to create a short form of the new Knee Society Knee Scoring System in order to reduce respondent burden. The authors applied sophisticated statistical methods that are informed by clinical guidance to carefully select items into the shorter form. As a result, they successfully reduced the new Knee Society Knee Scoring System from 17 items to six items. The authors established strong correlations between the original form and the shorter form domains and reasonable correlations with the SF-12 and KOOS scores. Finally, the authors This CORR Insights is a commentary on the article ‘‘The Knee Society Short Form Reduces Respondent Burden in the Assessment of Patient-reported Outcomes’’ by Scuderi and colleagues available at: DOI: 10.1007/s11999-015-4370-2. The author certifies that he, or any member of his immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons. This CORR Insights comment refers to the article available at DOI: 10.1007/s11999015-4370-2. H. Ghomrawi PhD, MPH (&) Division of Comparative Effectiveness and Outcomes Research, Department of Healthcare Policy and Research, Weill Medical College, Cornell University, 425 East 61st Street, Suite 301, New York, NY 10065, USA e-mail: hag2008@med.cornell.edu CORR Insights Published online: 3 July 2015 The Association of Bone and Joint Surgeons1 2015

Prof. Andrew D. Seidman: new opportunities for improving outcomes for breast cancer.

Andrew D. Seidman, M.D. (Figure 1) is an Attending Physician for the Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, and a Professor of Medicine, Joan and Sanford I. Weill Medical College of Cornell University. He is a medical oncologist with expertise in the management of both early stage and advanced breast cancer. His research interests include the clinical investigation of novel chemotherapeutic and targeted agents in the treatment of metastatic breast cancer.

Erotic Transfer in Borderline Personality Patients

Erotic Transfer in Borderline Personality Patients

The Prognostic Utility of the Current Risk Models in Predicting Outcomes of Patients (pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agents (HMA)

Background: Although HMA (azacitidine [aza] or decitabine [dac]) are standard of care therapies for HR-MDS pts, responses may not be seen for 4-6 months and occur in <50% of treated pts. Moreover, curative hematopoietic cell transplantation (HCT), which is recommended as up-front therapy for HR-MDS, is used in <5% of pts. The ability to identify pts with a low likelihood of benefiting from HMA who instead should receive immediate HCT or experimental treatment approaches is a clinical and research priority. Established MDS prognostic systems include the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R) [derived from untreated pt cohorts] and the MD Anderson Prognostic Scoring System (MDAPSS) [derived from treated and untreated pt cohort]. A French Prognostic Scoring System (FPSS) was developed to predict survival among aza-treated HR-MDS pts. We compared the relative prognostic discriminatory power of these models in a large cohort of HMA-treated pts with HR-MDS.Methods: The combined MDS database obtained from six institutions in the MDS Clinical Research Consortium (Moffitt Cancer Center, Cleveland Clinic, MD Anderson Cancer Center, Dana Farber Cancer Institute, Weill Medical College of Cornell University, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins) was used to identify patients with HR-MDS (IPSS intermediate-2 [INT-2] and high) who received HMA therapy (aza or dac). Responses were defined per International Working Group 2006 criteria. Overall response rate (ORR) was defined as the sum of rates of complete response (CR), partial response (PR), hematologic improvement (HI), and marrow CR. Pts with stable disease (SD) and progressive disease (PD) were considered non-responders. Logistic regression models were fitted and tested for association of response with prognostic risk categories using chi-square deviance tests. Overall survival (OS) was calculated from the time of diagnosis to time of death or last follow-up. Kaplan-Meier (KM) curves were generated for OS and the log-rank test was used to compare median OS. Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models.Results: We identified 595 pts with HR-MDS (70.3% with INT-2 and 29.7% with high IPSS) who received HMA as upfront therapy (83% aza, 17% dac). Median follow-up from diagnosis was 13.1 months (M), 95% confidence interval (CI): 11.5-15.1 M. 66% of pts were male, 88% white, 85% were >60 years, and 18% had therapy-related MDS. Median number of HMA cycles was 5.7 (range, 0.7-51) with 75% of pts receiving ≥3 cycles of therapy. Median time from diagnosis to start of HMA therapy was 1.5 M. ORR was 42.1% (CR 25.8%, PR 6.7%, HI-E 3.3%, HI-P 2.3%, HI-N 4.0%) while 57.2% were non-responders (SD 28.6% and PD 28.6%) and 0.7 were un-evaluable. None of the prognostic systems predicted overall response to HMA. Median OS for the entire cohort was 16.3 M (CI, 15.0-17.8 M). Figure 1 shows the KM survival curves and Table 1 shows the median OS, the corresponding CI and associated p-value for the risk categories in each prognostic model. Scores generated using the AIC (n=294) to assess the relative goodness of fit (lower is better) were 2139 (MDAPSS), 2148 (FPSS), 2155 (IPSS-R), and 2174 (IPSS).Conclusions: We report the largest direct comparison of the major MDS prognostic models among HMA-treated patients. None of the models predicted overall response to HMA therapy. Nonetheless, the IPSS-R, MDAPSS, and the FPSS all functioned well to separate HMA-treated pts with HR-MDS into different prognostic groups in terms of survival. The MDAPSS and FPSS appear superior to the IPSS-R and IPSS for survival prediction. HR-MDS pts with poor projected survival with HMA therapy should be considered for up-front HCT or for experimental approaches. [Display omitted] Abstract 1935. Table 1IPSS (n=595)IPSS-R (n=555)FPSS (n=296)MDAPSS (n=508)Risk Group (n)Median OS in months (CI)Risk Group (n)Median OS in months (CI)Risk Group (n)Median OS in months (CI)Risk Group (n)Median OS in months (CI)Low (0)NAVery low (1)NALow (19)38.4 (23.1-NR)Low (4)Not reached (NA)INT-1 (0)NALow (3)28.1 (27.0-NR)INT (241)17.8 (15.9-19.6)INT-1 (55)26.2 (18.8-40.4)INT-2 (418)16.8 (15.3-18.3)INT (59)39.1 (23.9-49.6)High (36)10.6 (7.2-13.4)INT-2 (143)18.6 (17.4-24.1)High (177)15.2 (13.4-17.8)High (197)18.8 (16.8-22.2)High (306)13.4 (11.8-15.0)Very High (295)12.2 (11.0-14.1)P-valueP=0.014P<0.0001P<0.0001P<0.0001 DisclosuresSekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen Corp: Membership on an entity’s Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity’s Board of Directors or advisory committees. Garcia-Manero:Novartis Pharma: Research Funding. Steensma:Amgen: Consultancy; Ariad: Equity Ownership; Celgene: Consultancy; Novartis: Consultancy. List:Celgene Corporation: Consultancy.

Response to TPO-Receptor Agonists: Role of Immature Platelet Fraction and Anti-GP1b

Background: Thrombocytopenia in Immune Thrombocytopenia (ITP) results from a combination of increased platelet destruction and reduced production, both often secondary to anti-platelet antibodies. Absolute immature platelet fraction (A-IPF) is a measure of young reticulated platelets in peripheral blood, and therefore provides an assessment of platelet production. Decreased platelet production in patients with ITP has been addressed by the recently developed Thrombopoietin Receptor Agonists (TPO-RA), which stimulate megakaryopoiesis and thereby, in responders, increase platelet production to a level which overcomes platelet destruction. The majority of ITP patients will respond to these agents, but which ones will respond is not known.Aims: To exploreA) whether baseline A-IPF levels are associated with platelet response to TPO–RA, andB) whether antibodies to platelet glycoproteins 1b or β3 influence the platelet response to TPO-RA.Methods: Platelet counts and A-IPF values were collected from patients treated with TPO-RA (n=91) at Weill Medical College of Cornell University until 2013. All available counts were included, and the median count for each month was determined pre-treatment, and at 1, 2, 3, 4, 5, and 6 months. Patients were divided by whether (n=20) or not (n=71) they often received rescue therapy (i.e. IVIG and/or daily steroids >10mg).The 71 patients who received minimal or no rescue treatment were deemed responders if the average of their six median monthly platelet counts doubled from baseline and was >50x109/L. Based on pretreatment A-IPF, patients were stratified into three cohorts: low (0-25), middle (26-40), and high (41+). Clinical variables such as age, splenectomy status, duration of ITP, and gender were also studied. The 20 “rescue” patients were similarly analyzed.The 84 patients with available sera had their antibody levels measured to GP1b and β3 by Elisa by Dr. Ni. Samples were sent to the lab and analyzed without knowledge of response status or associated A-IPF level. Patients were divided into four categories for analysis of their antiplatelet antibodies: positive for anti-ß3 antibody, positive for anti-GP1b, positive for both, or negative for both.Fisher’s exact, student t-, and chi-square tests were used to analyze differences in response to TPO-RA among patient groups, A-IPF levels, and anti-platelet antibodies.Results:71 Patients with Minimal Rescue TherapyFifty-nine of the 71 patients responded to TPO-RA. There was no significant difference in A-IPF values for responders and non-responders (p=0.95; Figure 1). A significant positive correlation was observed between increase in A-IPF over the 6-month period and response rate to TPO-RA (p=0.009). Age, gender, duration of ITP, and splenectomy status neither correlated with response rate, nor trended with A-IPF cohorts. [Display omitted] 20 Patients with Rescue TherapyFor the 20 patients who often received rescue therapy, low response rates were seen in the low A-IPF cohort and high response rates in the higher A-IPF cohorts. The percent of responders to treatment was higher in patients with chronic ITP than with newly diagnosed and persistent ITP (p= 0.04). Age, gender, and splenectomy status showed no relationship with response to TPO-RA. In comparison with the 71 patient group, the 20 patients presented lower response rates in all groups, with the exception of females.Anti-platelet AntibodiesThere was a weak correlation between A-IPF and anti-GP1b antibody levels (R=0.225), demonstrating that antibodies to GP1b may have a specific impact on platelet production.Patients who did not have detectable antibody to either GP1b or β3 responded better to TPO-RA than patients who tested positive for both Anti-GP1b and Anti-ß3 (p=0.003). The strongest correlation was observed between level of anti-GP1b and response to TPO-RA (p<0.001; Figure 2). [Display omitted] Conclusion:Rather than baseline A-IPF levels or clinical variables, the best predictor of good response to TPO-RA therapy was the absence of anti-GP1b and anti- β3 platelet antibodies, especially anti-GP1b. An explanation for the dominant effect of antibodies to GP1b is that stimulating megakaryopoiesis with TPO-RA would not effect a platelet increase as these antibodies may block proplatelet extension, preventing platelet release into the circulation. This may also explain the effect of anti-GP1b on response to steroids and IVIG. DisclosuresOff Label Use: Eltrombopag is a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. Use in children and adolescents will be discussed.. Bussel:Amgen: Equity Ownership; GSK: Equity Ownership; Amgen: Membership on an entity’s Board of Directors or advisory committees; GSK: Membership on an entity’s Board of Directors or advisory committees; Amgen: Research Funding; GSK: Research Funding; Sysmex: Research Funding.

Planned homebirth: not a Dutch treat for export.

FA Chervenak, LB McCullough, B Arabin, RL Brent, MI Levene, A Grunebaum a Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY, b Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA, c Center for Mother and Child, Philipps University, Marburg, d Clara Angela Foundation, Berlin, Germany, e Alfred I. DuPont Hospital for Children, Thomas Jefferson University, Wilmington, DE, USA f Division of Paediatrics & Child Health,University of Leeds, Leeds, UK

Editorial introductions

Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Sherif F. NaguehSherif F. NaguehAfter graduating from the Cairo University Faculty of Medicine, Egypt, in 1986, Dr Nagueh emigrated to Houston, Texas, USA. He completed his medicine residency and cardiology fellowship at Baylor College of Medicine, USA. He is currently Professor of Medicine at Weill Medical College of Cornell University, USA; and Medical Director of the Echocardiography Laboratory at the Methodist DeBakey Heart Center in Houston, Texas, USA. Dr Nagueh has received several awards, including the Second Annual Feigenbaum Lecture at the American Society of Echocardiography meeting in 2001. He sits on the Editorial Boards of the Journal of the American College of Cardiology, Circulation, Journal of the American Society of Echocardiography, and Clinical Science; and has served as the Imaging and echocardiography Section Editor for Current Opinion in Cardiology since 2001. Andrew PipeAndrew PipeDr Andrew Pipe graduated from Queen's University, Canada in 1974. He is currently Chief of the Division of Prevention and Rehabilitation at the University of Ottawa Heart Institute, Canada, and is also a Professor in the Faculty of Medicine at the University of Ottawa, Canada. He is currently involved in clinical research assessing new approaches to smoking cessation, strategies designed to facilitate exercise adoption, and novel initiatives to prevent cardiovascular disease. Dr Pipe has addressed audiences in over 30 nations and is frequently consulted on issues related to tobacco use and smoking cessation, physical activity and health, and drug use in sport. Dr Pipe is the recipient of the International Olympic Committee's Award for “Sport, Health and Wellbeing” and honourary degrees from Queen's University (LLD), Brock University (DSc), Canada and the University of Guelph (DSc), Canada. He was the recipient of the Canadian Cardiovascular Society's Dr Harold N. Segall Award for distinguished contributions to the prevention of cardiovascular disease, and was named to the Order of Canada in 2002.

Hypopigmented interface T-cell dyscrasia: a form of cutaneous T-cell dyscrasia distinct from hypopigmented mycosis fungoides.

Hypopigmentation in cutaneous T-cell lymphoproliferative disease should not always be equated with hypopigmented mycosis fungoides (MF). A form of hypopigmented pre-lymphomatous T-cell dyscrasia falling under the designation of the so-called hypopigmented interface variant of T-cell dyscrasia has recently been proposed. The aim of the present study was to establish hypopigmented interface T-cell dyscrasia as its own entity apart from other T-cell dyscrasias and MF using a patient case series. Twenty four cases of hypopigmented interface T-cell dyscrasia were identified in the dermatopathology database of Weill Medical College of Cornell University. There were 17 females and seven males (mean age, 36years). In children and adolescents, the patients were most commonly of African American extraction. Truncal photo-protected areas manifesting as large solitary patches or multiple smaller macules were characteristic; disease progression to MF occurred in only one patient. The lesions responded to topical steroids and light therapy. The pathology was defined by a cell poor interface associated with degeneration of keratinocytes and melanocytes, and by lymphocytes whose nuclei showed low-grade cerebriform atypia, and which expressed a significant reduction in CD7 and CD62L expression. In 50% of the cases, the implicated cell type was of the CD8 subset. Clonality was not identified. Hypopigmented interface T-cell dyscrasia is a distinct entity separate from and rarely progressive to MF.

Importance of cardiovascular disease risk management in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is commonly accompanied by other cardiovascular disease (CVD) risk factors, such as hypertension, obesity, and dyslipidemia. Furthermore, CVD is the most common cause of death in people with T2DM. It is therefore of critical importance to minimize the risk of macrovascular complications by carefully managing modifiable CVD risk factors in patients with T2DM. Therapeutic strategies should include lifestyle and pharmacological interventions targeting hyperglycemia, hypertension, dyslipidemia, obesity, cigarette smoking, physical inactivity, and prothrombotic factors. This article discusses the impact of modifying these CVD risk factors in the context of T2DM; the clinical evidence is summarized, and current guidelines are also discussed. The cardiovascular benefits of smoking cessation, increasing physical activity, and reducing low-density lipoprotein cholesterol and blood pressure are well established. For aspirin therapy, any cardiovascular benefits must be balanced against the associated bleeding risk, with current evidence supporting this strategy only in certain patients who are at increased CVD risk. Although overweight, obesity, and hyperglycemia are clearly associated with increased cardiovascular risk, the effect of their modification on this risk is less well defined by available clinical trial evidence. However, for glucose-lowering drugs, further evidence is expected from several ongoing cardiovascular outcome trials. Taken together, the evidence highlights the value of early intervention and targeting multiple risk factors with both lifestyle and pharmacological strategies to give the best chance of reducing macrovascular complications in the long term.

Lovers Lame

Back to table of contents Previous article Next article Communications and UpdatesFull AccessLovers LameRobert Michels, M.D.Robert MichelsSearch for more papers by this author, M.D.Published Online:1 Dec 2013https://doi.org/10.1176/appi.ajp.2013.13091205AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail by RudneyRobert. Bradenton, Fla., BookLocker.com, 2012, 272 pp., $15.26.David Levin, a government editor in his early forties, loses his job and has trouble finding a new one. He is single, has little confidence in his relations with women, but longs for a relationship. Finally, he embarks on one and is swept away only to be rejected. He is swept away again by a subsequent relationship only to be rejected once more. This time, he is faced with a frightening alternative: participate in his girlfriend’s kinky perversion, which puts him in a passive and feminine role, or she will terminate the relationship. He is tempted, sorely tempted, but declines.This crisis is symbolically linked to the major theme of the book. David has cerebral palsy. Throughout his life, he has repeatedly been confronted with painful choices: accept helpless, passive dependency in return for being cared for by others or seek empowerment, autonomy, and maturity with the risk of loneliness and the certainty of repeated failures. This book is about the life of the disabled—their community and their longing, frustration, pain, rage, depression, hope, hopelessness, and fundamental humanity.David joins and then becomes a leader of a self-help group of disabled persons (with cerebral palsy, spina bifida, multiple sclerosis, double amputation, deafness, blindness—the author goes out of his way to be inclusive). This provides an opportunity to present several character types and several styles of adaptation. His girlfriend, a member of the group, is an artist who has multiple sclerosis. She paints portraits of each of the other members, emphasizing both their individual characteristics and the stigmata of their disability. David is sensitive to critical differences, such as congenital versus adult acquired, but he is primarily sensitive to critical similarities. Their anger is pervasive—at employers, social agencies, doctors, therapists, families, the physically normal (they prefer “temporarily able-bodied”), each other, and, perhaps most of all, themselves. Their life challenges are the same as everyone else’s—career, relationships, sex, money, fun, creativity, spirituality, but for them each of these is further complicated by the two central truths of disability. There are things that others can do and that they cannot, and others see them as different, as belonging to a special stigmatized group. The burden is constant and at times overwhelming. Some are dramatically successful, many give up, and most live a mixture of the two.The author, Robert Rudney, has cerebral palsy. However, the book is not simply autobiographical, although Rudney’s personal experiences have obviously enriched it. He is a Dartmouth graduate, married with three children, who developed a self-help group for persons with cerebral palsy. (The broader population of disabled persons in the fictional group in the book allows him to expand his perspective.) The text frequently segues into discussions of barriers, employment, economic statistics, and the like, but the story (and particularly the romances) moves it along and reflects what happens in life—that we are all more human than otherwise and that those fundamental human issues structure our lives.New York, N.Y.Dr. Michels is the Walsh McDermott University Professor of Medicine and University Professor of Psychiatry at Weill Medical College of Cornell University, New York. FiguresReferencesCited byDetailsCited byNone Volume 170Issue 12 December 2013Pages 1502-1502 Metrics PDF download History Accepted 1 September 2013 Published online 1 December 2013 Published in print 1 December 2013

High morbidity and mortality found for high‐risk, non–muscle‐invasive bladder cancer

High morbidity and mortality found for high‐risk, non–muscle‐invasive bladder cancer

Robotic Prostatectomy in Urological Surgery: An Observership at Weill Medical College of Cornell University, New York

Robotic Prostatectomy in Urological Surgery: An Observership at Weill Medical College of Cornell University, New York

Professor William Jarnagin: biliary malignancy.

Professor William R. Jarnagin (Figure 1) served as the Hepatobiliary Fellow at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1996-97. Since 1997, he has been an attending surgeon at Memorial Sloan-Kettering Cancer Center, where he has served as Chief of the Hepatopancreatobiliary Service since 2008 and was a Vice-Chairman of the Department of Surgery from 2006-2010. He holds the Enid A. Haupt Chair in surgery at MSKCC and is Professor of Surgery at Weill Medical College of Cornell University.

Neuron Finding Tracks Path of RNA Decay

A newly discovered mechanism regulating how neurons find their way to the right connections—and how that can go wrong—may lead to better understanding of neurodevelopmental disorders.

Using principal-agent theory as a framework for analysis in evaluating the multiple stakeholders involved in the accreditation and quality assurance of international medical branch campuses

This article applies the theoretical framework of principal-agent theory in order to better understand the complex organisational relationships emerging between entities invested in the establishment and monitoring of cross-border international branch campus medical schools. Using the key constructs of principal-agent theory, information asymmetry and goal conflict, the article explores the multiple information asymmetries and potential goal conflicts that exist in the establishment of branch campus medical programmes. A review of the literature on international medical programme oversights revealed several considerations for organisations to contemplate in the physical movement of their institutions across borders. Using examples drawn from Weill Medical College in Qatar and Newcastle University Medicine Malaysia, the article illustrates how multiple overlapping agencies can provoke information asymmetry regarding quality standards and conflict of goals between the branch campus and the accrediting agencies. In the cases of international branch campuses, differentiating the principal and the agent is often difficult.