Kathleen T. Montone

Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients.

Background. Posttransplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus–associated malignancy that occurs in the setting of pharmacologic immunosuppression after organ transplantation. With the increased use of organ transplantation and intensive immunosuppression, this disease is becoming more common. We explore reduction in immunosuppression as an initial therapy for PTLD. Methods. We analyzed our organ transplant patient database to identify patients with biopsy-proven PTLD who were initially treated with reduction of their immunosuppressive medications with or without surgical resection of all known disease. Results. Forty-two adult patients were included in this study. Thirty patients were treated with reduction in immunosuppression alone. Twelve patients were treated with both reduction in immunosuppression and surgical resection of all known disease. Thirty-one of 42 patients (73.8%) achieved a complete remission. Of those patients who were treated with reduction in immunosuppression alone, 19 of 30 (63%) responded with a median time to documentation of response of 3.6 weeks. Multivariable analysis showed that elevated lactate dehydrogenase (LDH) ratio, organ dysfunction, and multi-organ involvement by PTLD were independent prognostic factors for lack of response to reduction in immunosuppression. In patients with none of these poor prognostic factors, 16 of 18 (89%) responded to reduction in immunosuppression in contrast to three of five (60%) with one risk factor and zero of seven (0%) with two to three factors present. The analysis also showed that increased age, elevated LDH ratio, severe organ dysfunction, presence of B symptoms (fever, night sweats, and weight loss), and multi-organ involvement by PTLD at the time of diagnosis are independent prognostic indicators for poor survival. With median follow-up of 147 weeks, 55% of patients are alive with 50% in complete remission. Conclusions. Reduction in immunosuppression is an effective initial therapy for PTLD. Clinical prognostic factors may allow clinicians to identify which patients are likely to respond to reduction in immuno- suppression.

Comprehensive Genomic Characterization of Long Non-coding RNAs across Human Cancers

The discovery of long non-coding RNA (lncRNA) has dramatically altered our understanding of cancer. Here, we describe a comprehensive analysis of lncRNA alterations at transcriptional, genomic, and epigenetic levels in 5,037 human tumor specimens across 13 cancer types from The Cancer Genome Atlas. Our results suggest that the expression and dysregulation of lncRNAs are highly cancer type specific compared with protein-coding genes. Using the integrative data generated by this analysis, we present a clinically guided small interfering RNA screening strategy and a co-expression analysis approach to identify cancer driver lncRNAs and predict their functions. This provides a resource for investigating lncRNAs in cancer and lays the groundwork for the development of new diagnostics and treatments.

A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer.

In a genome-wide survey on somatic copy-number alterations (SCNAs) of long noncoding RNA (lncRNA) in 2,394 tumor specimens from 12 cancer types, we found that about 21.8% of lncRNA genes were located in regions with focal SCNAs. By integrating bioinformatics analyses of lncRNA SCNAs and expression with functional screening assays, we identified an oncogene, focally amplified lncRNA on chromosome 1 (FAL1), whose copy number and expression are correlated with outcomes in ovarian cancer. FAL1 associates with the epigenetic repressor BMI1 and regulates its stability in order to modulate the transcription of a number of genes including CDKN1A. The oncogenic activity of FAL1 is partially attributable to its repression of p21. FAL1-specific siRNAs significantly inhibit tumor growth in vivo.

Biologic and Prognostic Significance of Dermal Ki67 Expression, Mitoses, and Tumorigenicity in Thin Invasive Cutaneous Melanoma

PURPOSE Tumor cell proliferation is a central feature of melanoma progression. In this study, we characterized three biomarkers of proliferation (Ki67 expression, dermal mitotic rate [MR], and tumorigenicity) in thin (< or = 1.00 mm) primary cutaneous melanomas and examined their association with prognosis. PATIENTS AND METHODS We used immunohistochemistry to determine Ki67 expression using the monoclonal antibody MIB-1 in lesions from a prospective cohort that included 396 patients with thin invasive primary melanomas seen between 1972 and 1991. A multivariate Cox proportional hazards model was used to define independent prognostic factors, and recursive partitioning was used to develop a prognostic tree identifying risk groups. RESULTS Dermal Ki67 expression was lower than epidermal Ki67 expression in radial growth phase (RGP) melanomas (n = 171), and dermal Ki67 expression and MR were higher in tumorigenic vertical growth phase (VGP) melanomas (n = 193) compared with RGP and nontumorigenic VGP melanomas (n = 42). Dermal Ki67 expression, MR greater than 0, growth phase, thickness, ulceration, tumor-infiltrating lymphocytes, and sex were associated with metastasis at 10 years, however, only dermal Ki67 expression, MR greater than 0, and sex were independent prognostic factors. Two high-risk groups were identified: men and women with dermal MR greater than 0 and dermal Ki67 expression > or = 20% in tumor cells and men with MR greater than 0 and Ki67 expression less than 20%, with 10-year metastasis rates of 39% and 20%, respectively. CONCLUSION Proliferation slows as melanoma cells enter the dermis and then increases with the onset of tumorigenic VGP. Ki67 expression and dermal MR provide independent prognostic information that can potentially be used in risk-based management of patients.

Histology and Histomorphometry of Ethmoid Bone in Chronic Rhinosinusitis

Mucosal changes have been well described in chronic sinusitis, yet little is known about the underlying bone, despite clinical and experimental evidence suggesting that bone may be involved in chronic sinusitis. Techniques of undecalcified bone analysis were used for detailed histologic examination of ethmoid bone in chronic sinusitis compared with controls. Bone synthesis, resorption, and inflammatory cell presence were specifically assessed. Additionally, histomorphometry techniques were used to determine ethmoid bone physiology in individuals undergoing surgery for chronic sinusitis. Overall, individuals undergoing surgery for chronic sinusitis were found to have evidence of marked acceleration in bone physiology with histologic changes including new bone formation, fibrosis, and presence of inflammatory cells. These findings are compared with osteomyelitis in long bone and the jaw. The suggestion that underlying bone may serve as a catalyst for chronic sinusitis is supported and implications for therapy are discussed.

Transoral Robotic Surgery Alone for Oropharyngeal Cancer: An Analysis of Local Control

OBJECTIVE To evaluate local control following transoral robotic surgery (TORS) with the da Vinci Surgical System (Intuitive Surgical Inc) as a single treatment modality for oropharyngeal squamous cell carcinoma (OSCC). DESIGN Prospective, single-center, observational study. SETTING Academic university health system and tertiary referral center. PATIENTS Thirty adults with previously untreated OSCC. INTERVENTION Transoral robotic surgery with staged neck dissection as indicated. MAIN OUTCOME MEASURES Local control and margin status. RESULTS Thirty patients were enrolled with previously untreated OSCC and no prior head and neck radiation therapy. Follow-up duration was at least 18 months. At the time of diagnosis, 9 tumors were T1 (30%); 16 were T2 (53%); 4 were T3 (13%); and 1 was T4a (3%). The anatomic sites of these primary tumors were tonsil in 14 (47%), tongue base in 9 (30%), glossotonsillar sulcus in 3 (10%), soft palate in 3 (10%), and oropharyngeal wall in 1 (3%). There was only 1 patient (3%) who had a positive margin after primary resection; further resection achieved a final negative margin. Perineural invasion was noted in 3 tumors (10%). No patient received postoperative adjuvant therapy. At a mean follow-up of 2.7 years (range, 1.5-5.1 years), there was 1 patient with local failure (3%). CONCLUSION As the only modality used for treatment of pathologically low-risk OSCCs, TORS provides high local control and is associated with low surgical morbidity.

Bone involvement in sinusitis : An apparent pathway for the spread of disease

Objectives/Hypothesis To study the effects of bone involvement in experimentally induced sinusitis and the effect of involved bone on the overlying mucosa.

The thyroid Hürthle (oncocytic) cell and its associated pathologic conditions: a surgical pathology and cytopathology review.

CONTEXT Hürthle cells are eosinophilic, follicular-derived cells that are associated with a variety of nonneoplastic and neoplastic thyroid lesions. The differential diagnosis of Hürthle cell lesions is quite broad. OBJECTIVE To review the pathologic conditions associated with Hürthle cells in the thyroid and to discuss pathology of thyroid lesions associated with oncocytic cytology. DATA SOURCES A variety of thyroid nonneoplastic (autoimmune thyroiditis, multinodular goiter) and neoplastic conditions (Hürthle cell adenoma, Hürthle cell carcinoma) are associated with Hürthle cell cytology. In addition, there are several thyroid neoplasms that should be considered when one observes a Hürthle cell neoplasm in the thyroid (oncocytic variant of medullary carcinoma, several variants of papillary thyroid carcinoma). CONCLUSIONS Oncocytic cytology is seen in a variety of thyroid conditions that are associated with a broad differential diagnosis and care must be used for accurate diagnosis. Newer molecular-based techniques may be useful for further classification of thyroid neoplasms with oncocytic pathology.

A Dendritic Cell Vaccine Pulsed with Autologous Hypochlorous Acid-Oxidized Ovarian Cancer Lysate Primes Effective Broad Antitumor Immunity: From Bench to Bedside

Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo. Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate–pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC. Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. Clin Cancer Res; 19(17); 4801–15. ©2013 AACR.

Ret oncogene activation in papillary thyroid carcinoma: Prevalence and implication on the histological parameters

The Ret proto-oncogene is known to be rearranged in papillary carcinoma of the thyroid. The aim of this study was to investigate the in situ expression of Ret mRNA in thyroid tumors. Formalin-fixed, paraffin-embedded tissue specimens from 45 thyroid lesions were examined by in situ hybridization using manual capillary action technology (MicroProbe Staining System) and a 52-base synthetic biotinylated oligonucleotide probe complementary to the tyrosine-kinase domain of Ret proto-oncogene. The clinicopathological features of these patients with thyroid lesions also were noted. Ret was noted in 17 (43%) of 40 papillary carcinomas. In contrast, none of the three follicular carcinomas, follicular adenoma, nodular hyperplasia, and normal thyroids, showed evidence of Ret mRNA. Our results showed that, in papillary thyroid carcinoma, there is an important role of Ret activation. The Ret staining could be a useful marker for papillary carcinoma.