Cervical Adenocarcinoma: A Comparison of the Reproducibility of the World Health Organization 2003 and 2014 Classifications.

OBJECTIVE: The aim of the study was to compare the reproducibility of malignant glandular tumors of the uterine cervix classified per World Health Organization (WHO) 2003 and 2014. MATERIALS AND METHODS: Two pathologists reviewed 228 cases composed of adenocarcinoma in situ and 22 adenocarcinoma histotypes and selected 405 representative hematoxylin and eosin slides, which were digitally scanned. Six other pathologists (3 gynecological and 3 anatomical) independently reviewed and classified the images per both WHO classifications. One year later, they classified a random sample of 25 cases. Inter- (inter-OR) and intra-observer (intra-OR) reproducibility of the 6 pathologists and separately for gynecological compared with anatomical pathologists was tested using κ statistics. RESULTS: Both classifications were collapsed into 6 categories as benign, adenocarcinoma in situ, and mucinous, endometrioid, rare, and adenosquamous-miscellaneous carcinomas. WHO 2014 had an additional category: endocervical adenocarcinoma, usual type. Inter-observer κ values were more reliable than the intra-OR results based on 95% CIs. The average inter-OR κ values with both classifications were moderate between the 6 pathologists and between the 3 anatomical pathologists. In contrast, they were substantial between the 3 gynecological pathologists. With both classifications, the average intra-OR κ values of the 6 pathologists and both pathologist groups trended toward substantial. CONCLUSIONS: Reproducibility among 6 pathologists is unaffected by changes in the WHO 2014 classification and averages moderate between different and trends toward substantial between the same pathologist. Reproducibility between different pathologists can improve to substantial when they have expertise in gynecological pathology.

Enumeration and Localization of Mesenchymal Progenitor Cells and Macrophages in Synovium from Normal Individuals and Patients with Pre-Osteoarthritis or Clinically Diagnosed Osteoarthritis.

Osteoarthritis (OA) is a degenerative disorder characterized by chondrocyte apoptosis and degeneration of articular cartilage resulting in loss of mobility and pain. Inflammation plays a key role in the development and progression of OA both on the side of apoptosis and repair, while its exact role in pathogenesis has yet to be fully elucidated. Few studies have examined the cellular composition (inflammatory cells and/or progenitor cells) in the synovium of patients with pre-OA (asymptomatic with cartilage damage). Therefore, in the current study, mesenchymal progenitor cells (MPCs) and macrophages were enumerated within normal, pre-OA and OA synovium. No differences were observed between MPCs in normal vs. pre-OA, however, fewer macrophages were observed in pre-OA vs. normal synovium. Osteoarthritic synovium contained greater numbers of both MPCs and macrophages. Interestingly, the localization of MPCs and macrophages was affected by disease severity. In normal and pre-OA synovium, MPCs and macrophages co-localized, while in OA synovium, MPCs and macrophage populations were spatially distinct. Examining the cellular interactions between MPCs and macrophages in synovium may be essential for understanding the role of these cells in the onset and/or pathogenesis of the disease. This study has provided a first step by examining these cell types both spatially and temporally (e.g., disease severity). Further cellular and molecular studies will be needed to determine the functions of these cells in the context of disease and in relation to each other and the joint as a whole.

REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors.

PURPOSE: This open-labeled, phase I clinical trial was designed to determine the safety and tolerability of percutaneous intralesional administration of wild-type oncolytic revovirus type 3 Dearing (Reolysin®) in cancer patients with accessible and evaluable disease, who had otherwise failed to improve on standard cancer interventions. EXPERIMENTAL DESIGN: An escalating dose of Reolysin® starting from up to 10(10) plague forming units (PFU) was administered to each cohort of three patients per dose level. Viral shedding, reovirus neutralizing antibody response, toxicity and clinical response were assessed. RESULTS: Nineteen patients with various advanced solid tumors were treated. The most common toxicities related to treatment were grade 2 (or less) local erythema and transient flu like symptoms. Viral shedding was not seen in cerebral spinal fluid (CSF), urine and stool samples in all patients. Rising viral antibody titres were seen in all patients. In addition, we observed some evidence of local target tumor response activity in 7/19 patients (37 %) at the end of six or more weeks follow-up, with one patient exhibiting a complete response (CR), two a partial response (PR), and four stable disease (SD) to the local injected lesion. CONCLUSIONS: Reolysin® is well tolerated given intralesionaly, with DLT/MTD not reached at a dose of 10(10) PFU. The favorable toxicity profile, lack of viral shedding and possible therapeutic activity has made this unattenuated oncolytic reovirus an attractive cancer therapeutic agent for ongoing clinical studies, including in the setting of locally advanced accessible disease for palliation of symptoms.

Primary signet-ring cell adenocarcinoma of the endometrium: case report and review of the literature.

Endometrial adenocarcinoma presenting with deep venous thrombosis is an exceptional event more typical of extra-mullerian primary tumors. Metastases to the spleen are also unusual in this setting. In addition, primary endometrial adenocarcinoma with signet-ring cell features has been reported only once. This study describes a case of primary endometrial carcinoma with prominent signet-ring cell features that presented in an unusual manner: with bilateral deep vein thromboses and splenic metastases. It is important for clinicians and pathologists to be aware of this entity; it may have an atypical clinical presentation and the histologic features raise a spectrum of differential diagnoses.

Microstructural damage in arterial tissue exposed to repeated tensile strains.

OBJECTIVES: Vertebral artery (VA) damage has been anecdotally linked to high-speed, low-amplitude spinal manipulative treatments (SMTs) of the neck. Apart from a single study quantifying the maximum stresses and strains imposed on the VA during cervical SMT, there are no data on the mechanics of the VA for this treatment modality, and there is no information on the possible long-term effects of repeat exposure to cervical SMT. The purpose of this study was to quantify microstructural damage in arterial tissue exposed to repeat strain loading of a magnitude similar to the maximum strains measured in the VA during high-speed, low-amplitude cervical SMT. METHODS: Twenty-four test specimens from cadaveric rabbit ascending aorta were divided into 2 control groups (n = 12) and 2 experimental groups (n = 6 each). Specimens were exposed to 1000 strain cycles of 0.06 and 0.30 of their in situ length. A pathologist, blinded to the experimental groups, assessed microstructural changes in the arteries using quantitative histology. Pearson chi(2) analysis (alpha = .05) was used to assess differences in tissue microstructure between groups. RESULTS: Control and 0.06 strain tissues were statistically the same (P = .406), whereas the 0.30 strain group showed microstructural damage beyond that seen in the control group (P = .024). CONCLUSIONS: We conclude that cadaveric rabbit arterial tissue similar in size and mechanical properties of that of the human VA can withstand repeat strains of magnitudes and rates similar to those measured in the cadaveric VA during cervical SMT without incurring microstructural damage beyond control levels.

Desmoids: a revelation in biology and treatment.

INTRODUCTION: Using a preoperative neoadjuvant chemoradiation protocol, followed by complete excision, we have achieved local control rates exceeding that found in most large series. METHODS: From October 1990 through May 2008, resectable desmoids were initially treated with a preoperative protocol using Adriamycin 30 mg x 3 days continuous intravenous infusion followed by 3,000 cGy of radiation (300 cGy fractions over 10 days). Resection was performed 4-6 weeks later. After 2001, all patients were initially offered Tamoxifen 120 mg/day and Celebrex 400 mg/day for 1 year. Patients who progressed on Tamox/Celeb were treated with protocol and those with stabilization or regression were observed. Patient demographics, tumor size, history of previous recurrences, and follow-up status were recorded prospectively. RESULTS: There were 40 females and 12 males with a mean follow-up of 45 months. Forty patients presented with primary tumors and eight presented with recurrent disease. Thirty-nine patients had surgical resection and 13 were observed. Thirty patients underwent the neoadjuvant protocol. Tamoxifen and Celebrex were used in 16 patients, 6 had stabilization in growth, 1 had a 50% reduction in the size of the tumor, there was 1 complete regression, and 8 progressed. Of the patients who had resectable disease Tamoxifen and Celebrex obviated surgery in 30%. Overall 13% (5) of patients developed a recurrence. There were three recurrences among the protocol group for a local control rate of 90%. CONCLUSION: Although our neoadjuvant protocol demonstrates the best results to date in eradication of disease, an initial conservative approach is reasonable to determine who would most benefit from surgery.

Costs associated with diffuse large B-cell lymphoma patient treatment in a Canadian integrated cancer care center.

OBJECTIVE: The objective of this study was to provide a detailed comparative microcosting analysis for two cancer treatment pathways to contribute evidence for resource allocation and operational decision-making in a Canadian cancer care context. METHODS: We estimated direct medical costs (in 2004 CAN$) of the entire pathway of care for diffuse large B-cell lymphoma (DLBCL) patients in a large Canadian cancer treatment center. Patient samples were defined as those who received R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; n = 85) or CHOP (i.e., without rituximab; n = 86) as first-line treatment. All subsequent treatments including palliative care for these patient samples were assessed. Hospitalization costs and unit costs of medical resources were collected from integrated medical organizations. Individual patient resource consumption was assessed via medical chart review. RESULTS: For first-line treatment, drug cost was the largest contributor to total cost, followed by hospitalization cost. Rituximab was the largest contributor to mean cost differences between R-CHOP and CHOP treatments. For treatments subsequent to first-line treatment, no significant cost differences were found. Hospitalization and transplantation costs were the two largest constituents of total costs subsequent to first-line treatment, followed by drug cost. Patients with advanced stage disease cost significantly more than patients with limited stage disease. CONCLUSION: This is the first detailed microcosting study that has employed consistent local data to estimate total medical costs for DLBCL patients in Canada. This information is useful for resource allocation planning and operational decisions, because it provides more substantive, relevant evidence as compared to aggregated, literature or extrapolated information.

Chondroblastoma: An Update.

Chondroblastoma is a rare primary bone tumor of young people that typically arises in the ends of the long bones. Radiologic investigations show a small, circumscribed, lytic lesion. The tumor is characterized histologically by the proliferation of chondroblasts along with areas of mature cartilage, giant cells, and occasionally, secondary aneurysmal bone cyst formation. Chondroblastoma, however, may also present with atypical features, such as prominent hemosiderin deposition, numerous giant cells, or the presence of a large aneurysmal bone cyst component. Malignant entities such as clear cell chondrosarcoma and chondroblastic osteosarcoma must also be considered. Recently, immunohistochemical stains such as DOG1 and SOX9 have been described in chondroblastoma, and K36M mutations in either the H3F3A or H3F3B genes have also been identified. While generally regarded as a benign entity, chondroblastoma manifests an intermediate type of behavior, given its ability to recur locally, and rarely, metastasize.

Adhesive-Enhanced Sternal Closure: Feasibility and Safety of Late Sternal Reentry.

This clinical case report describes sternal reentry performed years after adhesive-enhanced sternal closure using Kryptonite bone cement. This report provides novel data on the late effects of this innovation. We observed that sternal reentry is feasible and safe. The adhesive did not weaken from biodegradation over a period of several years. There was no evidence of adherence to adjacent soft tissues or other nonbony deep mediastinal structures. Surgeons who receive patients who require redoing cardiac surgery after adhesive-enhanced closure with Kryptonite can be reassured that sternal reentry is safe and feasible.

Reovirus oncolysis of human breast cancer.

We have previously shown that human reovirus replication is restricted to cells with an activated Ras pathway, and that reovirus could be used as an effective oncolytic agent against human glioblastoma xenografts. This study examines in more detail the feasibility of reovirus as a therapeutic for breast cancer, a subset of cancer in which direct activating mutations in the ras proto-oncogene are rare, and yet where unregulated stimulation of Ras signaling pathways is important in the pathogenesis of the disease. We demonstrate herein the efficient lysis of breast tumor-derived cell lines by the virus, whereas normal breast cells resist infection in vitro. In vivo studies of reovirus breast cancer therapy reveal that viral administration could cause tumor regression in an MDA-MB-435S mammary fat pad model in severe combined immunodeficient mice. Reovirus could also effect regression of tumors remote from the injection site in an MDA-MB-468 bilateral tumor model, raising the possibility of systemic therapy of breast cancer by the oncolytic agent. Finally, the ability of reovirus to act against primary breast tumor samples not propagated as cell lines was evaluated; we found that reovirus could indeed replicate in ex vivo surgical specimens. Overall, reovirus shows promise as a potential breast cancer therapeutic.

Mutation or polymorphism of the CD20 gene is not associated with the response to R-CHOP in diffuse large B cell lymphoma patients.

BACKGROUND: Rituximab, a chimeric antibody targeted to the human CD20 molecule, is a major component of the R-CHOP protocol used to treat patients with diffuse large B cell lymphoma (DLBCL). It is also a very expensive drug. Though the response rate of R-CHOP is higher than that of CHOP alone, patients may still experience a poor response. One possible mechanism that may mediate the poor response to R-CHOP is poor binding of the drug to the CD20 molecule, perhaps due to mutations or polymorphisms of the CD20 gene that affect its structure. To test this hypothesis and perhaps define a new predictor of R-CHOP response, our pilot study evaluated the CD20 gene sequence from patients exhibiting a poor outcome to R-CHOP. METHODS: Eleven patients with DLBCL who exhibited a recurrence of their disease and/or died within 24 months of R-CHOP treatment were categorized as showing poor progression-free survival (poor outcomes). Paraffin-embedded tissue specimens from the original tumors were evaluated for mutations or polymorphisms of the CD20 gene. Furthermore, sections from these patients and as well as from matched control patients who were categorized as good outcome patients (no progression of their disease within 36 months) were stained with anti-CD20 antibody and compared for CD20 protein expression. RESULTS: DNA sequence analyses revealed that no mutations were observed in DNA from the coding region of the CD20 gene in any of the initial tumors from 11 patients who showed poor outcomes with R-CHOP therapy. One case showed a synonymous single nucleotide polymorphism in exon 2 (C216T; rs2070770; Ile>>Ile). No significant differences in CD20 expression was observed between good and poor outcome patients with R-CHOP. CONCLUSIONS: Our results do not support association of CD20 mutations in specimens of the initial tumor or structural polymorphisms of the CD20 gene with patients who exhibited poor outcomes to R-CHOP.

Extra-axial chordoma.

Chordomas are low-grade malignant tumors of bone that occur almost exclusively in the axial skeleton. Other neoplasms with a similar histologic picture but an extra-axial location have been described, including parachordoma, myxoid chondrosarcoma, and extra-axial chordoma. We herein present another case of the rare extra-axial chordoma. A 41-year-old woman developed an 8.3 cm mass in the pubic bone. The gross, microscopic, and immunohistochemical findings were identical to those of a classic chordoma. Parachordoma and myxoid chondrosarcoma were excluded from the differential diagnosis. Five previously reported cases of extra-axial chordoma were reviewed and found also to demonstrate clinical and pathologic features specific to chordoma, despite arising in an extra-axial location. Although rare, extra-axial chordoma does exist and should be recognized and managed in a similar fashion to its well-described counterpart. It must be differentiated from other histologic mimics, because the treatment and prognosis can differ significantly.

Evaluation of conventional subciliary incision used in blepharoplasty: preoperative and postoperative videography and electromyography findings.

BACKGROUND: The purpose of this study was to evaluate the innervation and function of the orbicularis oculi area clinically, with video imaging, and electrically, with electromyography, before and after lower-eyelid blepharoplasty using a conventional subciliary incision. METHODS: Nine patients (18 eyes) were studied before and 4 to 12 weeks after lower-eyelid blepharoplasty. Video imaging documented clinical changes in involuntary (blink) and voluntary (squeeze and squint) eyelid function as well as resting lid position and tone. Electromyography was performed using concentric needle electrodes (25 mm in length, 0.03 mm in diameter) placed in the lateral and medial subciliary orbicularis oculi. A total of 36 sites in nine patients (four sites per patient) were studied. Acute denervation was identified by the presence of fasciculation; fibrillation potentials; insertional activity; sharp waves; and grade based on standard electromyography techniques. All patients underwent lower-eyelid blepharoplasty with a subciliary incision, skin-muscle flap and canthal anchoring with canthopexy or cantholysis, and canthoplasty. RESULTS: Video imaging of the lower eyelid before and after blepharoplasty showed evidence of eyelid malposition or abnormal voluntary or involuntary orbicularis oculi muscle function. There was no evidence of acute denervation in 34 of 36 sites (94 percent). Two patients had abnormal fasciculation in the left lateral position on two of 36 sites (6 percent). Thirty-three weeks postoperatively, one patient was retested and a normal electromyography result was obtained. CONCLUSIONS: This study demonstrated that lower-lid malposition or abnormal function after lower-lid blepharoplasty cannot be explained by denervation of the zygomatic branch of the facial nerve. Any acute or residual denervation seen in the subciliary orbicularis is not clinically significant. The importance of lower-lid support and canthal anchoring cannot be emphasized enough in preventing lower-lid malposition. Blepharoplasty is a challenging procedure that requires careful preoperative planning, intraoperative reassessment, and meticulous surgical technique to optimize facial rejuvenation and patient safety.

Upper eyelid reconstruction.

There are several options available for upper eyelid reconstruction that depend on the extent of involvement of the anterior and posterior lamella. Knowledge of the anatomy will ensure that in addition to the creation of an aesthetically acceptable eyelid reconstruction, a functional upper lid will be restored. The purpose of this article is to outline the anatomy of the eyelid, to analyze the components of eyelid defects, and to provide options for lid reconstruction.

A cutaneous manifestation of antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome is a disease defined by the presence of a hypercoagulable clinical state in association with antiphospholipid antibodies. This syndrome can involve large-vessel thrombosis or thrombotic microangiopathy. Approximately 40% of patients will present with a cutaneous manifestation as the first indication of this disease, with a marked number of patients concurrently developing multiorgan involvement. The authors present a patient with extensive cutaneous necrosis-a devastating sequela of antiphospholipid antibody syndrome. Additionally, multiorgan involvement developed, requiring systemic anticoagulation and supportive care. When medically stable, plastic surgical intervention was necessary to treat extensive areas of cutaneous necrosis. Widespread cutaneous necrosis is a rare but known sequela of this syndrome. Studies have demonstrated that prophylaxis for thrombosis is not effective. However, long-term medical management with oral anticoagulants has been shown to reduce the risk of recurrent thrombosis. Occasionally, plastic surgical intervention is needed to treat the sequelae of this disease. Therefore, knowledge of the presentation and manifestations of this disease is critical in the early detection and prompt treatment of patients to prevent life-threatening consequences of this catastrophic disease process.

Loss of heterozygosity associated with uniparental disomy in breast carcinoma.

Loss of heterozygosity is commonly assumed to be due to deletion of the appropriate genomic region in one chromosome within a neoplastic cell but may be due to other mechanisms such as mitotic non-disjunction or somatic recombination leading to uniparental heterodisomy. We chose to study the genomic regions surrounding the p53 and RB1 tumor suppressor genes in breast carcinoma to evaluate the different mechanisms that could mediate loss of heterozygosity. A microsatellite analysis of polymorphic markers in 50 breast cancer samples showed loss of heterozygosity for at least 1 of the 10 markers analyzed in 50% of the tumors studied, and an overall 8.47% of the informative loci showed loss of heterozygosity. All of the cases with loss of heterozygosity were further analyzed for gene copy number of the tumor suppressor genes RB1 and p53 by fluorescence in situ hybridization of either tumor touch preparations or microdissected tumor nuclei with specific genomic probes. Surprisingly, all samples showed the presence of both copies of tumor suppressor genes, including 4/50 cases showing loss of heterozygosity of tumor suppressor gene-spanning markers. One of the 4 cases showed loss of heterozygosity of markers spanning a distance of 6 cM over the RB1 gene, with normal copy numbers of the gene. Three other cases showed loss of heterozygosity of markers within the tumor suppressor gene (RBI or p53) and at least one other spanning marker. No cases showed a simultaneous reduction to homozygosity of markers both near the tumor suppressor gene and distal loci. We suggest that the presence of both copies of the tumor suppressor gene in the cases with loss of heterozygosity of spanning markers and internal markers for that tumor suppressor gene could be explained by somatic recombination resulting in uniparental disomy, but not mitotic nondisjunction or deletion. As the mechanism for physical deletion of a chromosome may be different from those mediating somatic recombination, study of this phenomenon may identify different pathways of genomic instability that may be of diagnostic or treatment significance in breast or other cancers, particularly in those treatments based upon DNA-altering agents.