Paulie Papavassiliou

Handoffs in the era of duty hours reform: A focused review and strategy to address changes in the accreditation council for graduate medical education common program requirements

With changes in the Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements related to transitions in care effective July 1, 2011, sponsoring institutions and training programs must develop a common structure for transitions in care as well as comprehensive curricula to teach and evaluate patient handoffs. In response to these changes, within the Duke University Health System, the resident-led Graduate Medical Education Patient Safety and Quality Council performed a focused review of the handoffs literature and developed a plan for comprehensive handoff education and evaluation for residents and fellows at Duke. The authors present the results of their focused review, concentrating on the three areas of new ACGME expectations--structure, education, and evaluation--and describe how their findings informed the broader initiative to comprehensively address transitions in care managed by residents and fellows. The process of developing both institution-level and program-level initiatives is reviewed, including the development of an interdisciplinary minimal data set for handoff core content, training and education programs, and an evaluation strategy. The authors believe the final plan fully addresses both Dukes internal goals and the revised ACGME Common Program Requirements and may serve as a model for other institutions to comprehensively address transitions in care and to incorporate resident and fellow leadership into a broad, health-system-level quality improvement initiative.

Ataxia-Telangiectasia Group D Complementing Gene (ATDC) Promotes Lung Cancer Cell Proliferation by Activating NF-κB Pathway

Previous studies suggested Ataxia-telangiectasia group D complementing gene (ATDC) as an oncogene in many types of cancer. However, its expression and biological functions in non-small cell lung cancer (NSCLC) remain unclear. Herein, we investigated its expression pattern in 109 cases of human NSCLC samples by immunohistochemistry and found that ATDC was overexpressed in 62 of 109 NSCLC samples (56.88%). ATDC overexpression correlated with histological type (p<0.0001), tumor status (p = 0.0227) and histological differentiation (p = 0.0002). Next, we overexpressed ATDC in normal human bronchial epithelial cell line HBE and depleted its expression in NSCLC cell lines A549 and H1299. MTT and colony formation assay showed that ATDC overexpression promoted cell proliferation while its depletion inhibited cell growth. Furthermore, cell cycle analysis showed that ATDC overexpression decreased the percentage of cells in G1 phase and increased the percentage of cells in S phase, while ATDC siRNA treatment increased the G1 phase percentage and decreased the S phase percentage. Further study revealed that ATDC overexpression could up-regulate cyclin D1 and c-Myc expression in HBE cells while its depletion down-regulated cyclin D1 and c-Myc expression in A549 and H1299 cells. In addition, ATDC overexpression was also associated with an increased proliferation index, cyclin D1 and c-Myc expression in human NSCLC samples. Further experiments demonstrated that ATDC up-regulated cyclin D1 and c-Myc expression independent of wnt/β-catenin or p53 signaling pathway. Interestingly, ATDC overexpression increased NF-κB reporter luciferase activity and p-IκB protein level. Correspondingly, NF-κB inhibitor blocked the effect of ATDC on up-regulation of cyclin D1 and c-Myc. In conclusion, we demonstrated that ATDC could promote lung cancer proliferation through NF-κB induced up-regulation of cyclin D1 and c-Myc.

Composite lymphoid neoplasm of B-cell and T-cell origins: a pathologic study of 14 cases ☆ ☆☆ ★

We retrospectively analyzed 14 composite lymphoma/lymphoid neoplasms (CL) of B-cell/T-cell origins. These consisted of a spectrum of T-cell neoplasms in combination with different B-cell lymphomas/leukemias, with peripheral T-cell lymphoma and diffuse large B-cell lymphoma encountered most frequently for each respective neoplastic lineage. Histopathologic evaluation demonstrated 6 patterns of neoplastic distribution, including zone, inverted zone, diffuse mixed, regional/nodular mixed, compartmental, and segmental distributions. Four of 9 cases studied were positive for Epstein-Barr virus, all with a mixed pattern, suggesting that this pattern may predict an Epstein-Barr virus association. None of 14 cases was considered CL at the initial histologic evaluation. Only 6 (46.2%) of 13 cases had coexisting B-cell/T-cell neoplasms highlighted by immunohistochemistry, and the other 7 (53.8%) cases had 1 or both of the neoplastic components hidden. Flow cytometry detected both neoplastic lineages in 4 (44%) but failed to detect a clonal B-cell population in 4 (44%) and missed neoplastic T cells in 1 (11.1%) of 9 cases. Molecular testing detected clonal rearrangement of IGH/K gene in 11 (84.6%) of 13 cases, and clonal rearrangement of the TCRG/B gene in 13 (92.9%) of 14 cases, including 8 with identical amplicons detected in separate samples. CLs of B-cell/T-cell origin are heterogeneous in subtype combination and topographic pattern, often with one of the components histologically occult. A multidisciplinary approach is emphasized to establish a definitive diagnosis in these challenging cases.

A malignant lymphoma with histological features and immunophenotypic profile intermediate between EBV-positive diffuse large B-cell lymphoma and EBV-positive classical Hodgkin lymphoma in a 67-year-old female: a "gray zone" lymphoma associated with Epstein-Barr virus in the elderly.

Epstein-Barr virus (EBV) can be associated with both classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma of the B-cell type, particularly in immunodeficient patients or elderly individuals. While polymorphic variants of EBV-positive large B-cell lymphoma (EBV+ DLBCL) frequently resemble cHL in morphology, and thereby may cause diagnostic difficulty, a true gray zone lymphoma with overlapping morphological and immunophenotypical features of EBV+ DLBCL and EBV+ cHL has not been reported in the literature. We describe a unique case of an EBV+ malignant lymphoma of B-cell origin with hybrid features of EBV+ DLBCL and EBV+ cHL in a 67-year-old female without an identifiable etiology for immunodeficiency. The biopsy of an enlarged lymph node showed a polymorphic infiltrate containing Reed-Sternberg-like pleomorphic large cells, which were positive for CD30 and CD15. Although CD20 was negative and PAX5 and CD45 were down-regulated, the pleomorphic large cells expressed multiple other B-cell antigens which are characteristically absent in cHL. EBV-encoded RNA hybridization (EBER) studies demonstrated nuclear reactivity in the large cells as well as in the smaller bystander cells. A clonal rearrangement of the immunoglobulin heavy chain gene was also detected by PCR. Although the results of the EBV and genotypic studies suggest this case may be an example of EBV+ DLBCL of the elderly instead of EBV+ cHL, the immunophenotype is strikingly ambiguous. Thus, this case may represent an interface between EBV+ DLBCL and EBV+ cHL.

Resected pancreatic neuroendocrine tumors: patterns of failure and disease-related outcomes with or without radiotherapy.

PURPOSE Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution. METHODS Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. RESULTS Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10). CONCLUSIONS The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

Dishevelled‐3 activates p65 to upregulate p120‐catenin transcription via a p38‐dependent pathway in non‐small cell lung cancer

Dishevelled‐3 (Dvl‐3) and p120‐catenin (p120ctn) have abnormal expression in non‐small cell lung cancer (NSCLC), which is associated with poor prognosis. Dvl‐3 upregulates p120ctn transcription in NSCLC cells, but the mechanism is unknown. Here we transiently transfected Dvl‐3 cDNA to NSCLC cells. Dvl‐3 transfection is sufficient for induction of p38 signaling. In turn, Dvl‐3 induces p38‐mediated activation of the p65 so as to facilitate its nuclear translocation. Treatment with SB203580 (p38 inhibitor) or BAY 11‐7082 (IκB‐α phosphorylation inhibitor) suppresses Dvl‐3 induced activation of p65. The results further show that active p65 interacts with PAX2 promoter to increase the expression of PAX2 and then PAX2 binds to p120ctn promoter so as to upregulate p120ctn gene transcription. Moreover, Dvl‐3 transfection enhanced the binding of active p65 to Sp1 so as to decrease the binding of Sp1 to p120ctn promoter. The above‐mentioned effects are linked to biological behavior of non‐small cell lung cancer cells. These findings confirm that p38 and PAX2 are important for the Dvl‐3 induced upregulation of p120ctn. Dvl‐3 activates a p38 → p65 → PAX2 → p120ctn pathway to affect biological behavior of NSCLC cells.

Metachronous/concomitant B-cell neoplasms with discordant light-chain or heavy-chain isotype restrictions: evidence of distinct B-cell neoplasms rather than clonal evolutions.

Metachronous/concomitant B-cell neoplasms with distinct morphology are usually considered clonally related. We retrospectively analyzed 4 cases of metachronous/concomitant B-cell neoplasms with discordant light-chain/heavy-chain restrictions. The primary diagnoses included chronic lymphocytic leukemia (CLL; n = 2), lymphoplasmacytic lymphoma (n = 1), and pediatric follicular lymphoma (FL; n = 1). The respective secondary diagnoses included diffuse large B-cell lymphoma (DLBCL; n = 2), plasmablastic myeloma, and pediatric FL. The secondary B-cell neoplasm occurred after the primary diagnosis in 3 cases, with the median interval of 120 months (range, 21-216), whereas the remaining 1 case had the 2 neoplasms (CLL/DLBCL) diagnosed concurrently. Histology suggested aggressive transformation in 3 cases and recurrence in 1 case (FL). Nonetheless, 3 cases showed discordant light-chain restrictions between the 2 B-cell neoplasms, whereas in the remaining case (lymphoplasmacytic lymphoma/plasmablastic myeloma), the 2 neoplasms shared κ light-chain restriction but expressed different heavy-chain isotypes (IgM versus IgA). The 2 CLL/DLBCL cases had polymerase chain reaction-based IGH/K gene rearrangement study and amplicon sequence analysis performed, which demonstrated distinct clonal amplicons between the 2 B-cell neoplasms in each case. Concomitant/metachronous B-cell neoplasms may be clonally unrelated, which can be confirmed by immunoglobulin isotype analysis and/or genotypic studies. We advocate analysis of clonal identities in large cell transformation or recurrent disease compared with primary indolent B-cell neoplasm because of a potential difference in prognosis between clonally related and unrelated secondary B-cell neoplasms.

An Epstein-Barr virus-positive diffuse large B-cell lymphoma presenting as multi-organ failure: a catastrophic lymphomatosis with fulminant visceral organ dissemination resulting in a precipitous death in a 59-year-old female with no identifiable etiology for immunodeficiency.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is an aggressive B-cell neoplasm related to age-associated impaired immunity. We report such a case in a 59-year-old woman with a catastrophic disease course. The patient initially presented with fever, fatigue, malaise and weakness over one-week period. Despite empirical treatment with antibiotics and antiviral agents, she subsequently developed multi-organ failure and coagulopathy. Radiographic imaging revealed hepatomegaly, splenomegaly, pleural effusion, and ascites. Her complete blood cell count showed marked leukocytosis, anemia and thrombocytopenia. Morphologic examination of blood smear demonstrated many abnormal plasmacytoid lymphocytes, and flow cytometric analysis detected an intermediate-large mature B-cell population (69%) without detectable surface immunoglobulin. High copy numbers of EBV genome were detected in the blood by PCR. A diagnosis of EBV+ DLBCL, leukemic phase, was made. Despite aggressive treatment and supportive care, the patient succumbed to multi-organ failure one week after initial presentation. Autopsy demonstrated EBV+ DLBCL infiltration in all the organs examined. This case describes an unusual presentation of EBV+ DLBCL and highlights the necessity of pertinent ancillary tests to avoid delay in the diagnosis and treatment.

T-cell prolymphocytic leukemia in a 63-year-old female with a pre-existing T-cell large granular lymphocytic leukemia: metachronous T-cell leukemias with discordant subset restrictions (CD4 versus CD8) and distinct clonal identities.

A 55-year-old female with T-cell large granular lymphocytic leukemia (T-LGL) (CD8+) was initially treated with anti-thymocyte globulin and then cyclosporine due to anemia/neutropenia. While the severity of cytopenia varied with the therapy, the T-LGL persisted. Eight years after the initial diagnosis, she developed lymphadenopathy and hepatosplenomegaly. A complete blood cell count revealed leukocytosis, anemia and thrombocytopenia with ∼ 80% lymphocytes. In contrast to the LGL cells, the blood lymphocytes at this time were medium-large in size and had oval/irregular nuclei, condensed chromatin, indistinct nucleoli and a moderate amount of basophilic cytoplasm, many with elongated vacuoles, and some with cytoplasmic projections. The abnormal lymphocytes comprised ∼ 30% of the bone marrow cellularity with interstitial infiltrates/aggregates. Immunophenotypic analyses demonstrated a T-cell neoplasm with features suggestive of T-cell prolymphocytic leukemia (T-PLL) (CD4+). Cytogenetic analysis revealed a novel clone with complex abnormalities. PCR-based TRG gene rearrangement studies detected a clonal amplicon distinct from that of the preexisting T-LGL. Because of the chronological sequence of the two T-cell neoplasms, this case was initially considered an aggressive transformation of T-LGL. However, this was ultimately excluded by a discordant CD4-subset restriction and the presence of a distinct clonal identity. While these two T-cell neoplasms may have intrinsic connections, the underlying pathogenesis remains to be investigated.

Resected pancreatic neuroendocrine tumors: Patterns of failure and disease-related outcomes with or without radiotherapy.

325 Background: Pancreatic neuroendocrine tumors (NET) are rare with improved prognosis compared to adenocarcinomas. Surgical resection remains the standard of care although many patients present with unresectable/metastatic disease. While many resected patients will fail distantly, little is known regarding the use of adjuvant radiotherapy. To define this and establish specific patterns of failure, an analysis of resected patients from a single institution was performed. METHODS From 1994 to 2009, 33 patients with NET of the pancreatic head underwent resection with curative intent at Duke University. Sixteen patients were treated with surgical resection alone, and an additional 17 underwent resection with adjuvant (n=10) or neoadjuvant (n=7) radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. RESULTS Patients receiving radiation therapy were more likely to have involved nodes (47% vs 19%, p=0.09), more mitoses per high power field (p=0.10) and involved margins (47% vs 31%, p=0.20) compared to surgery alone patients. Median survival for the whole cohort was 52 months. Two-year survival was 68% for the CMT group and 93% for the surgery alone group (p=0.03). Two-year local control was 85% for the CMT and 90% for the surgery group (p=0.49). Two-year metastasis-free survival was 45% and 69% for the CMT and surgery patients, respectively (p=0.02). CONCLUSIONS Patients receiving CMT were more likely to have adverse pathologic features compared to surgery-alone patients. Survival outcomes were high in both groups, although less so in the CMT group. Distant metastasis development dominated patterns of failure. Local failure following resection of NETs is uncommon, and the role of adjuvant radiotherapy in this setting remains unclear. No significant financial relationships to disclose.