Lawrence R Zukerberg

Harvard Medical School, Boston, Massachusetts, United States

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Publications (144)1714.55 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Current immunohistochemical and in situ hybridization (ISH) assays are generally inconclusive for clonality unless plasmacytic differentiation is present. This study examined a series of cytology specimens and explored the ability of a branched-chain RNA (bRNA) ISH assay for immunoglobulin κ constant (IGKC) and immunoglobulin λ constant (IGLC) to detect a clonal population of B lymphocytes. Methods: Pathology databases were used to identify fine-needle aspiration biopsies (n = 28) and exfoliative cytology samples (n = 20). Demographic, flow cytometry, and excision biopsy results were recorded. bRNA ISH was performed on the Leica Bond platform with the following probes: IGKC, IGLC, immunoglobulin λ-like polypeptide 5 (IGLL5), and a housekeeping gene (HKG). Results: The bRNA ISH assay was validated with 30 surgical biopsies. On bRNA ISH, a clonal B-cell population (light-chain ratio > 10:1) was detected in 22 of 28 cases with a final diagnosis of lymphoma. In 2 cases, a κ predominance was present, although the ratio was <10:1. Eleven of the 17 κ-clonal lymphomas also expressed IGLL5, the latter recognized by the presence of an intranuclear signal. Two B-cell lymphomas lacked IGKC and IGLC, whereas 2 cases were negative for the HKG. In 12 of the 20 cases with reactive lymphoid tissue, bRNA ISH identified a polyclonal lymphoid population. No light-chain messenger RNA was detected in 6 cases (typically those associated with very few B cells). Conclusions: The automated bRNA ISH platform is a robust technique for detecting a clonal B-cell population in cytology material. Cancer (Cancer Cytopathol) 2015. © 2015 American Cancer Society.
    Cancer Cytopathology 11/2015; DOI:10.1002/cncy.21629 · 3.35 Impact Factor
  • Lawrence Zukerberg · Krishnan Mahadevan · Martin Selig · Vikram Deshpande ·
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    ABSTRACT: Aims: We explore the utility of an IgG4 immunohistochemical stain to help distinguish eosinophilic esophagitis (EoE) from gastroesophageal reflux disease (GERD). Methods: We examine 21 cases of EoE and 25 cases of GERD. The diagnosis of EoE was based on the presence of esophageal dysfunction, greater than 15 eosinophils per high-power field, and a lack of response to proton pump inhibitors. GERD showed intraepithelial eosinophils but with clinical and/or histologic response to proton pump inhibitor therapy. We also evaluated an additional cohort of 22 cases with intraepithelial eosinophils. An immunohistochemical stain for IgG4 was performed. Results: Sixteen of 21 (76%) of cases with EoE showed intrasquamous extracellular IgG4 deposits while all 25 cases of GERD were negative. Mucosal IgG4 positive plasma cells were identified in EoE and GERD cases in 58% and 40% of cases, respectively. EoE patients on treatment were less likely to be positive for intraepithelial IgG4 deposits (88% versus 53%). On the validation cohort, the sensitivity and specificity for EoE was 88% and 100%, respectively. Conclusions: The presence of intrasquamous IgG4 deposits is a useful adjunctive marker in the distinction between EoE and GERD This article is protected by copyright. All rights reserved.
    Histopathology 10/2015; DOI:10.1111/his.12892 · 3.45 Impact Factor
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    ABSTRACT: Objectives: Human herpesvirus 8 (HHV8)-associated lymphomas are uncommon, mainly affect men infected with the human immunodeficiency virus (HIV), and usually have a poor prognosis. We sought to characterize the HHV8+ lymphomas seen at our institution since the mid-1990s. Methods: We identified 15 patients with HHV8-associated lymphomas and evaluated their clinical and pathologic features. Results: Diagnoses included primary effusion lymphoma (PEL) (n = 2), extracavitary PEL (n = 8), intravascular large B-cell lymphoma (n = 1), HHV8+ plasmablastic microlymphoma (n = 3), and germinotropic lymphoproliferative disorder (GLD) (n = 1). The case of GLD progressed to a high-grade HHV8+ Epstein-Barr virus-positive lymphoma, an evolution that has not been previously reported. Four patients were HIV-(three from an HHV8-endemic area). Potentially misleading pathologic features in our series of extracavitary PEL included classic Hodgkin lymphoma-like features, lymph node sinus involvement, and T-cell antigen expression. Conclusions: HHV8-associated lymphomas can be clinically and pathologically heterogeneous, with features that may lead to misdiagnosis as other types of lymphoma.
    American Journal of Clinical Pathology 12/2014; 142(6):816-29. DOI:10.1309/AJCPULI3W6WUGGPY · 2.51 Impact Factor
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    ABSTRACT: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common antibody-mediated limbic encephalitis and is associated with underlying ovarian teratoma. Previous studies suggest that expression of NMDAR on teratoma neural tissue initiates an autoimmune response to NMDAR in the brain. As some teratomas of patients with anti-NMDAR encephalitis lack neuronal tissue, we questioned if there could be an alternate mechanism of the disease. We performed immunohistochemical analyses for NMDAR and correlated its expression with histology on 10 control teratomas and 5 teratomas associated with anti-NMDAR encephalitis. Both control and case teratomas expressed NMDAR-bearing neural tissue. All 15 teratomas contained large amounts of NMDAR bearing squamous epithelium; in 2 cases this was the only tissue expressing NMDAR. NMDAR-bearing neural tissue is not the sole source of encephalitis in all patients. Furthermore, we speculate that NMDAR expression by squamous epithelium may contribute to the disease development in some patients.
    International Journal of Gynecological Pathology 11/2014; 33(6):598-606. DOI:10.1097/PGP.0000000000000104 · 1.67 Impact Factor
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    Aliyah R. Sohani · Lawrence R. Zukerberg ·
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    ABSTRACT: Various subtypes of small B-cell lymphoma can involve the spleen, and their classification in splenectomy specimens may be challenging. Accurate diagnosis of these entities may be critical to ensuring appropriate treatment and prognostication. We describe the types of small B-cell lymphoma that may involve the spleen and their differential diagnosis, using splenic compartment of involvement (white pulp vs. red pulp) as a diagnostic framework. Published literature on various lymphomas of the spleen, with an emphasis on recently recognized entities and emerging molecular genetic data, is reviewed. A multifaceted approach to diagnosis, using clinical and laboratory data, morphology, immunophenotype, and molecular genetic testing, is discussed. Although relatively few small B-cell lymphoma entities involve the spleen primarily, many systemic lymphomas may involve the spleen secondarily, and some recently described entities are encountered with relative infrequency. Fortunately, an understanding of the unique anatomy of the spleen as reflected by its unusual diversity of functions, in concert with a multiparameter approach to diagnosis, can help in narrowing this broad differential diagnosis considerably, in order to reach a specific diagnosis with certainty.
    09/2014; 7(3):109-121. DOI:10.1007/s12308-014-0208-1
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    ABSTRACT: Background Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C + BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Results In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5–10 compared to the linear growth observed in vehicle treated tumors (p < 0.04 in all experiments). Tumor resurgence manifested between days 14–25 (p < 0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p < 0.05). Synergistic tumor growth suppression (p < 0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. Conclusions Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.
    Gynecologic Oncology 05/2014; 133(2). DOI:10.1016/j.ygyno.2014.02.022 · 3.77 Impact Factor
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    ABSTRACT: The KRAS oncogene influences angiogenesis, metastasis and chemoresistance in colorectal cancers (CRCs), and these processes are all enhanced in hypoxic conditions. To define functional activities of mutant KRAS in a hypoxic microenvironment, we first performed cDNA microarray experiments in isogenic DKs5 and DKO3 colon cancer cell lines that differ only by their expression of mutant KRAS (K-ras(D13) ). Adrenomedullin (ADM) was identified as one of the most significantly upregulated genes in DKs5 cells that express the KRAS oncogene in hypoxia (3.2-fold, p = 1.47 × 10(-5) ). Ectopic expression of mutant KRAS (K-ras(V12) ) in Caco-2 cells (K-ras(WT) ) induced ADM, whereas selective knockdown of mutant KRAS alleles (K-ras(D13) or K-ras(V12) ) in HCT116, DLD1 and SW480 colon cancer cells suppressed the expression of ADM in hypoxia. Knockdown of ADM in colon tumor xenografts blocked angiogenesis and stimulated apoptosis, resulting in tumor suppression. Furthermore, ADM also regulated colon cancer cell invasion in vitro. Among 56 patients with CRC, significantly higher expression levels of ADM were observed in samples harboring a KRAS mutation. Collectively, ADM is a new target of oncogenic KRAS in the setting of hypoxia. This observation suggests that therapeutic targets may differ depending upon the specific tumor microenvironment.
    International Journal of Cancer 05/2014; 134(9):2041-50. DOI:10.1002/ijc.28542 · 5.09 Impact Factor
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    ABSTRACT: Hirschsprung disease-associated enterocolitis (HAEC) leads to significant mortality and morbidity, but its pathogenesis remains unknown. Changes in the colonic epithelium related to goblet cells and the luminal mucus layer have been postulated to play a key role. Here we show that the colonic epithelium of both aganglionic and ganglionic segments are altered in patients and in mice with Hirschsprung disease (HSCR). Structurally, goblet cells were altered with increased goblet cell number and reduced intracellular mucins in the distal colon of biopsies from patients with HSCR. Endothelin receptor B (Ednrb) mutant mice showed increased goblet cell number and size and increased cell proliferation compared to wild-type mice in aganglionic segments, and reduced goblet cell size and number in ganglionic segments. Functionally, compared to littermates, Ednrb-/- mice showed increased transepithelial resistance, reduced stool water content and similar chloride secretion in the distal colon. Transcript levels of goblet cell differentiation factors SPDEF and Math1 were increased in the distal colon of Ednrb-/- mice. Both distal colon from Ednrb mice and biopsies from HSCR patients showed reduced Muc4 expression as compared to controls, but similar expression of Muc2. Particle tracking studies showed that mucus from Ednrb-/- mice provided a more significant barrier to diffusion of 200 nm nanoparticles as compared to wild-type mice. These results suggest that aganglionosis is associated with increased goblet cell proliferation and differentiation and subsequent altered surface mucus properties, prior to the development of inflammation in the distal colon epithelium. Restoration of normal goblet cell function and mucus layer properties in the colonic epithelium may represent a therapeutic strategy for prevention of HAEC.
    PLoS ONE 05/2014; 9(6):e99944. DOI:10.1371/journal.pone.0099944 · 3.23 Impact Factor
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    ABSTRACT: Resection without adjuvant therapy results in a low recurrence rate for patients with stage I (T1/2 N0) rectal cancer in the range of 4% to 16% at 5 years. There are limited data, however, regarding clinical or pathologic prognostic markers for recurrence in this population. The aim of this study is to assess the clinical and pathologic factors associated with local recurrence and overall survival in patients with early-stage rectal cancer after resection. This is a retrospective study. This study was conducted at 2 tertiary care centers in Boston, Massachusetts. From 2000 to 2008, 175 patients with stage I rectal cancer treated with local or total mesorectal excision without adjuvant therapy were identified. Time to local recurrence after resection and overall survival were evaluated for all patients with complete follow-up data. Perioperative data were reviewed to identify staging method, preoperative CEA, type of surgery, tumor size, number of lymph nodes resected, histological grade, circumferential resection margin, perineural invasion, lymphovascular invasion, and tumor ulceration. Data were analyzed by using a Cox proportional hazards regression model. Of the eligible cohort, 137 patients had complete follow-up data for analysis of time to local recurrence, and only 23 (16.8%) patients had local recurrence. Among these 23 patients, the median time to recurrence was 1.1 years (0.1-7.8). On multivariate analysis, male sex, current alcohol use, and tumor ulceration were associated with heightened risk of local recurrence. Of the original cohort, 173 patients had complete follow-up for overall survival analysis. Among these patients, the median overall survival was 12 years. On multivariable analysis, age at diagnosis >65 years and T2 pathologic stage were associated with decreased survival. As in any retrospective study, there is a potential for selection bias. Several patients were excluded from the analysis due to inadequate follow-up data. These results from two academic medical centers with specialized colorectal surgeons may not be generally applicable. The relatively small number of events, ie, recurrences, suggest the findings should be validated in a larger study. For patients with stage I rectal cancer treated with resection alone, these results provide important prognostic information and may help identify those who could benefit from additional therapy.
    Diseases of the Colon & Rectum 04/2014; 57(4):449-459. DOI:10.1097/DCR.0b013e3182a70709 · 3.75 Impact Factor
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    ABSTRACT: Endoscopic ampullectomy is increasingly performed in patients with familial adenomatous polyposis (FAP)-associated ampullary adenomas. We sought to define the procedure-associated morbidities and long-term outcomes. We performed a retrospective chart review of patients with FAP who underwent endoscopic ampullectomy at two tertiary institutions between 1999 and 2010. The severity of duodenal polyposis was classified according to Spigelman's classification. Of 26 FAP patients who underwent endoscopic ampullectomy, 21 arose in the setting of Spigelman's stage II duodenal polyposis. Adverse events associated with endoscopic ampullectomy included acute pancreatitis (19.2 %), abdominal pain (7.6 %), and bleeding (3.8 %). The mean resected adenoma size was 0.99 ± 0.34 cm. Three adenomas (12.0 %) contained foci of high-grade dysplasia. Follow-up data were available for 24 patients. The mean follow-up duration was 84.5 ± 36.2 months. Adenoma recurrence was observed in 14 patients (58.3 %; 14/24) at a mean of 38.3 months after initial ampullectomy. Adenomas ≥10 mm recurred more frequently than smaller adenomas (76.9 vs. 36.4 %; p = 0.002). Positive margins were not associated with higher recurrence rates. No cancers were observed during long-term follow-up. Three patients underwent a Whipple procedure, but none was performed for a recurrent ampullary adenoma. Endoscopic ampullectomy in FAP can be performed safely. Because ampullary adenomas frequently recur after endoscopic ampullectomy, close surveillance is essential. Smaller tumors are less likely to recur, suggesting a benefit for early recognition of these lesions.
    Surgical Endoscopy 02/2014; 28(8). DOI:10.1007/s00464-014-3467-0 · 3.26 Impact Factor
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    ABSTRACT: Bell shaped nuclei of metakaryotic cells double their DNA content during and after symmetric and asymmetric amitotic fissions rather than in the separate, pre-mitotic S-phase of eukaryotic cells. A parsimonious hypothesis was tested that the two anti-parallel strands of each chromatid DNA helix were first segregated as ssDNA-containing complexes into sister nuclei then copied to recreate a dsDNA genome. Metakaryotic nuclei that were treated during amitosis with RNase A and stained with acridine orange or fluorescent antibody to ssDNA revealed large amounts of ssDNA. Without RNase treatment metakaryotic nuclei in amitosis stained strongly with an antibody complex specific to dsRNA/DNA. Images of amitotic figures co-stained with dsRNA/DNA antibody and DAPI indicated that the entire interphase dsDNA genome (B-form helices) was transformed into two dsRNA/DNA genomes (A-form helices) that were segregated in the daughter cell nuclei then retransformed into dsDNA. As this process segregates DNA strands of opposite polarity in sister cells it hypothetically offers a sequential switching mechanism within the diverging stem cell lineages of development.
    Organogenesis 01/2014; 10(1). DOI:10.4161/org.27684 · 2.80 Impact Factor
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    ABSTRACT: Diagnosing anal squamous cell carcinoma (SCC), which is often preceded by anal intraepithelial neoplasia (AIN), may be challenging in small biopsies. Cytokeratin 17 (CK17) is a basal/myoepithelial cell keratin induced in activated keratinocytes and associated with disease progression in SCC of the uterine cervix, esophagus, and oral cavity. We investigated the utility of CK17 in diagnosing invasion in anal squamous neoplastic lesions. Immunohistochemical staining for CK17 was evaluated in 11 AINs, 12 invasive SCCs, 8 invasive SCCs with basaloid features (BSCC), and 2 invasive pure basaloid carcinomas. The pattern of staining was scored as surface/central, peripheral/rim, diffuse, or absent. All cases of invasive SCC and BSCC stained positive for CK17. Eleven of 12 (92%) SCCs showed diffuse staining, and 1 of 12 (8%) showed peripheral staining. Six of 8 (75%) BSCCs showed diffuse staining, and 2 of 8 (25%) showed peripheral staining. Both pure basaloid carcinomas were negative for CK17. One of 11 (9%) AINs was diffusely positive for CK17; all other AINs had surface or absent CK17. Of the 6 patients with concurrent AIN and invasive carcinoma, superficial expression of CK17 was present in 1 AIN, whereas all invasive components showed diffuse staining. The sensitivity and specificity of CK17 for identifying invasion in SCC and BSCC was 100% and 91%, respectively. Peripheral or diffuse staining for CK17 is a useful marker of invasion in anal squamous neoplastic lesions. A potential pitfall in the utility of CK17 is that the pure basaloid variant of anal carcinoma is negative for CK17.
    The American journal of surgical pathology 01/2014; 38(1):78-85. DOI:10.1097/PAS.0000000000000111 · 5.15 Impact Factor
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    ABSTRACT: Context.-Basaloid squamous cell carcinoma (bSCC) is an uncommon variant of squamous cell carcinoma, which may overlap histologically with basal cell carcinoma with squamous metaplasia (BCCm). Objective.-To aid in the differentiation of these neoplasms using immunohistochemical staining because of the worse prognosis associated with bSCC. Design.-Using immunohistochemical techniques, we investigated BerEp4, cytokeratin 17 (CK17), and cytokeratin 14 (CK14) protein expression in 25 cases of bSCC (8 cutaneous [32%], 12 aerodigestive tract [48%], and 5 lymph node metastases [20%]) and 43 cases of BCCm (39 cutaneous [91%], and 4 metastases [9%]). An immunoreactivity score was assigned using the percentage of tumor cells staining and the pattern of expression. Interobserver agreement for 2 independent pathologists was assessed using a κ coefficient. Results.-The mean percentage of staining was significantly higher in BCCm, compared with bSCC (BerEp4, P = .006; CK17, P < .001; CK14, P < .001; unpaired t test), with 58% of BCCm cases (25 of 43) displaying diffuse staining for all markers, and nearly all (98%; 42 of 43) displaying diffuse staining for CK17 and CK14. In contrast, no bSCC cases (0%) displayed diffuse staining for all 3 markers, and only 8% (2 of 25) displayed diffuse staining for CK17 and CK14. High interobserver agreement was determined. Conclusions.-BerEp4 alone is unreliable for differentiation between BCCm and bSCC, and the addition of either CK14 or CK17 will augment the sensitivity and negative predictive value of BerEp4 staining in BCCm and bSCC diagnosis.
    Archives of pathology & laboratory medicine 11/2013; 137(11):1591-8. DOI:10.5858/arpa.2012-0424-OA · 2.84 Impact Factor
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    ABSTRACT: The transformation of colonic mucosal epithelium to adenocarcinoma requires progressive oncogene activation and tumor suppressor gene inactivation. Loss of chromosome 18q is common in colon cancer but not in precancerous adenomas. A few candidate tumor suppressor genes have been identified in this region, including CABLES1 at 18q11.2-12.1. This study investigates the role of CABLES1 in an in vivo mouse model of intestinal adenocarcinoma and in human colon cancer cell culture. Apc (Min/+) mice were crossed with mice harboring targeted inactivation of the Cables1 gene (Cables1 (-/-) ). The intestinal tumor burden and tumor expression of β-catenin and PCNA was compared in Cables1 (+/+) Apc (Min/+) and Cables1 (-/-) Apc (Min/+) mice. β-catenin activity in human colon cancer cells with CABLES1 inactivation and intestinal progenitor cell function in Cables1 (-/-) mice were assayed in vitro. The mean number of small intestinal tumors per mouse was 3.1 ± 0.6 in Cables1 (+/+) Apc (Min/+) mice, compared with 32.4 ± 3.5 in the Cables1 (-/-) Apc (Min/+) mice (p < 0.0001). Fewer colonic tumors were observed in Cables1 (+/+) Apc (Min/+) mice (mean 0.6 ± 0.1) compared with the Cables1 (-/-) Apc (Min/+) mice (mean 1.3 ± 0.3, p = 0.01). Tumors from Cables1 (-/-) Apc (Min/+) mice demonstrated increased nuclear expression of β-catenin and an increased number of PCNA-positive cells. In vitro studies revealed that CABLES1 deficiency increased β-catenin dependent transcription and increased intestinal progenitor cell activity. Loss of Cables1 enhances tumor progression in the Apc (Min/+) mouse model and activates the Wnt/β-catenin signaling pathway. Cables1 is a tumor suppressor gene on chromosome 18q in this in vivo mouse model and likely has a similar role in human colon cancer.
    Cancer biology & therapy 05/2013; 14(7). DOI:10.4161/cbt.25089 · 3.07 Impact Factor
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    ABSTRACT: Profiling studies of mRNA and microRNA, particularly microarray-based studies, have been extensively used to create compendia of genes that are preferentially expressed in the immune system. In some instances, functional studies have been subsequently pursued. Recent efforts such as the Encyclopedia of DNA Elements have demonstrated the benefit of coupling RNA sequencing analysis with information from expressed sequence tags (ESTs) for transcriptomic analysis. However, the full characterization and identification of transcripts that function as modulators of human immune responses remains incomplete. In this study, we demonstrate that an integrated analysis of human ESTs provides a robust platform to identify the immune transcriptome. Beyond recovering a reference set of immune-enriched genes and providing large-scale cross-validation of previous microarray studies, we discovered hundreds of novel genes preferentially expressed in the immune system, including noncoding RNAs. As a result, we have established the Immunogene database, representing an integrated EST road map of gene expression in human immune cells, which can be used to further investigate the function of coding and noncoding genes in the immune system. Using this approach, we have uncovered a unique metabolic gene signature of human macrophages and identified PRDM15 as a novel overexpressed gene in human lymphomas. Thus, we demonstrate the utility of EST profiling as a basis for further deconstruction of physiologic and pathologic immune processes.
    The Journal of Immunology 04/2013; 190(11). DOI:10.4049/jimmunol.1203471 · 4.92 Impact Factor
  • Leigh H Simmons · Alexander R Guimaraes · Lawrence R Zukerberg ·
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    ABSTRACT: A 54-year-old man was admitted to this hospital because of recurrent diarrhea, vomiting, and weight loss. The initial episode of diarrhea occurred 2.5 years before admission. Diagnostic procedures were performed.
    New England Journal of Medicine 02/2013; 368(8):757-65. DOI:10.1056/NEJMcpc1208149 · 55.87 Impact Factor
  • Ravi B Parikh · George A Alba · Lawrence R Zukerberg ·

    Gastroenterology 12/2012; 144(2). DOI:10.1053/j.gastro.2012.08.025 · 16.72 Impact Factor
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    ABSTRACT: Pediatric follicular lymphoma (PFL) is a variant of follicular lymphoma (FL) presenting as localized lymphadenopathy in children. Unlike conventional adult FL, PFL typically does not recur or progress. Clear diagnostic criteria for PFL are lacking, and it is uncertain whether this indolent lymphoma is defined by age or may occur in adults. We analyzed 27 FL in patients < 40 years of age and found that all 21 cases that lacked a BCL2 gene abnormality (BCL2-N; P < .0001) and had > 30% Ki67 fraction (high proliferation index, HPI; P = .0007) were stage I and did not progress or recur; in comparison, all 6 cases with BCL2 rearrangement and/or PI < 30% were stage III/IV, and 5 of 6 recurred or progressed. In a separate cohort of 58 adult FL (≥ 18 years of age), all 13 BCL2-N/HPI cases were stage I, and none progressed or relapsed, whereas 11 of 15 stage I cases with BCL2 gene abnormality and/or LPI relapsed or progressed (P = .0001). The adult and pediatric BCL2-N/HPI FL cases had similar morphologic features. Our results confirm the highly indolent behavior of PFL and suggest that these are characterized by HPI and absence of BCL2 gene abnormality. PFL-like cases also occur in adults and are associated with indolent behavior in this patient population.
    Blood 07/2012; 120(12):2395-404. DOI:10.1182/blood-2012-05-429514 · 10.45 Impact Factor
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    ABSTRACT: The diagnosis of infectious mononucleosis (acute Epstein-Barr virus (EBV) infection) is usually made on the basis of clinical and laboratory findings. However, an atypical clinical presentation occasionally results in a lymph node or tonsillar biopsy. The morphological features of EBV-infected lymphoid tissue can easily mimic lymphoma. Furthermore, the immunophenotype of the immunoblasts has not been well characterized. To assess the morphological spectrum of acute EBV infection and the utility of immunohistochemistry in diagnosing difficult cases that resemble lymphoma, we reviewed 18 cases of acute EBV infection submitted in consultation to our institution with an initial diagnosis of/or suspicion for lymphoma. Patients included nine male and nine female individuals with a median age of 18 years (range 9-69). Biopsies were obtained from lymph nodes (3/18) or Waldeyer's ring (15/18). Infectious mononucleosis was confirmed by monospot or serological assays in 72% of cases (13/18). All cases featured architectural distortion by a polymorphous infiltrate with an immunoblastic proliferation, sometimes forming sheets. Reed-Sternberg-like cells were present in 8/18 (44%) of the cases. Infiltrates were often accompanied by necrosis (10/18) and mucosal ulceration (6/15). The majority of immunoblasts in all cases were CD20+ B cells with a post-germinal center immunophenotype (strongly positive for MUM1/IRF4 (18/18), CD10- (18/18 negative) and BCL-6- (16/18 negative; 2/18 faint BCL-6 expression in <10% of immunoblasts)). Immunoblasts showed variable weak expression of BCL-2 and polyclonal expression of κ and λ immunoglobulin light chains in 81% cases. Reed-Sternberg-like cells in 8/8 cases were CD30+, CD15-, BOB.1+ and OCT-2+. In conclusion, an atypical lymphoid infiltrate with numerous MUM1+, CD10-, BCL-6- immunoblasts should raise the suspicion of a reactive process, such as infectious mononucleosis, and warrants additional consideration before a diagnosis of lymphoma is made.
    Modern Pathology 05/2012; 25(8):1149-59. DOI:10.1038/modpathol.2012.70 · 6.19 Impact Factor
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    ABSTRACT: How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.
    Nature 05/2012; 486(7404):490-5. DOI:10.1038/nature11163 · 41.46 Impact Factor

Publication Stats

6k Citations
1,714.55 Total Impact Points


  • 1990-2015
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1992-2014
    • Massachusetts General Hospital
      • • Department of Pathology
      • • Department of Medicine
      • • Laboratory of Molecular Endocrinology
      Boston, Massachusetts, United States
  • 1992-2013
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2012
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 2011
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2004
    • Brigham and Women's Hospital
      • Division of Hematology
      Boston, MA, United States
  • 2003
    • Roswell Park Cancer Institute
      • Department of Pathology
      Buffalo, New York, United States
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, California, United States
  • 2001
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1999
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
  • 1995
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States