Yisheng V. Fang

Tissue inhibitor of metalloproteinase-1 modulates allergic lung inflammation in murine asthma

Matrix metalloproteinases (MMPs) modulate development, inflammation, and repair in lungs. Tissue inhibitors of MMPs (TIMPs) interact with MMPs, controlling the intensity and nature of the response to injury. Absence of MMP-9, -2, and -8 activities is associated with altered lung inflammation during allergic sensitization. To test the hypothesis that the absence of TIMP-1 enhances allergic lung inflammation, airway hyperreactivity (AHR), and lung remodeling in asthma, we studied TIMP-1 null (TIMP-1 KO) mice and their WT controls using an ovalbumin (OVA) asthma model. TIMP-1 KO mice, compared to WT controls, developed an asthma phenotype characterized by AHR, pronounced cellular lung infiltrates, greater reduction in lung compliance, enhanced Th2 cytokine mRNA and protein expression, and altered collagen lung content associated with enhanced MMP-9 activity. Our findings support the hypothesis that TIMP-1 plays a protective role by preventing AHR and modulating inflammation, remodeling, and cytokine expression in an animal model of asthma.

Modulatory effect of neoadjuvant chemotherapy on biomarkers expression; assessment by digital image analysis and relationship to residual cancer burden in patients with invasive breast cancer

The use of digital imaging techniques for biomarker assessment has gained recognition as a valid tool for clinical use. In this study, we used image analysis for evaluation of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2), Ki-67 index, and p53 in 172 patients with invasive breast cancer treated with neoadjuvant chemotherapy and compared it with an untreated group (100 cases). We also examined the relationship between biomarker expression and the extent of residual disease using the Web-based MD Anderson residual cancer burden (RCB) calculator. Residual disease was classified as RCB 0/I, II, and III corresponding to complete/near-complete response, moderate, and extensive residual disease, respectively. Overall change in ER, PR, and HER2 status in the treated group was seen in 9.02% (P = .0148), 18.4% (P = .011), and 12.0% (P = .0042), respectively. Change in HER2 status, positive to negative and negative to positive, occurred in 27.2% and 7.0%, respectively. The group with RCB 0/I was frequently younger (P = .0057) and showed higher ER(-) status (P = .0316), lower ER scores (P = .0103), higher Ki-67 index (P = .0008), and p53 (P = .0055) compared with those with RCB II and III. Pathologic tumor stage (P = .0072), lumpectomy versus mastectomy (P = .0048), and p53 expression (P = .0190) were independent predictors of recurrence-free survival. The RCB categories (P = .0003) and tumor grade (P = .0049) were independent predictors of overall survival. This is the first study to conduct a comprehensive analysis of biomarkers in neoadjuvant chemotherapy-treated patients versus an untreated group using the digital image analysis method. We have demonstrated for the first time the relationship between RCB, tumor biomarkers expression, and clinical outcome.

Ossifying fibroma of the nose and paranasal sinuses

The purpose of this work was to perform a systematic review regarding ossifying fibroma and its multiple variants of the paranasal sinuses, and to identify any clinical differences between the multiple variants.

Induction chemotherapy followed by concurrent chemoradiotherapy for advanced stage oropharyngeal squamous cell carcinoma with hpv and p16 testing

Objective: The objective was to report our experience with advanced stage oropharyngeal squamous cell carcinoma treated sequentially with induction chemotherapy followed by concurrent chemoradiotherapy. Methods: Retrospective chart review identified 49 eligible patients with advanced stage oropharyngeal squamous cell carcinoma treated with induction chemotherapy followed by concurrent chemoradiotherapy. HPV and p16INK4A testing was performed on pathology specimens. Follow-up of over 11 months was required unless a death or treatment failure occurred before that time. Results: Treatment with induction chemotherapy followed by concurrent chemoradiotherapy resulted in 44/48 (90%) complete durable response. One death occurred from pulmonary embolism. Toxicity profiles were comparable to other published data. Average follow-up was 3.9 years. Oncologic failure rates among subgroups showed 5.7% failure for HPV+/p16+ cancer, 9.1% failure for HPV-/p16+ cancer, 100% failure for HPV-/p16- cancer, 0% failure for nonsmokers, and 17.9% failure for smokers. Conclusions: This study showed favorable outcomes in terms of durable oncologic response and acceptable toxicity profiles. It is notable that 36/49 patients were HPV+/p16+ and 11/49 were HPV-/p16+. Only 2 patients were HPV-/p16-, and both died as a result of oncologic failures. This highlights the importance of obtaining HPV and p16 testing in studies evaluating the efficacy of treatments for oropharyngeal squamous cell carcinoma.

Uterine myometrium as a cell patch as an alternative graft for transplantation to infarcted cardiac myocardium : A preliminary study

Purpose Currently, only a small fraction of patients are able to receive reperfusion therapy for myocardial infarctions. We hypothesize that myometrial cell patch transplantation could be an alternative approach for the treatment of myocardial infarction. Design We performed a preliminary study to determine the feasibility of this novel therapeutic approach in a rabbit model. Procedures Six adult female New Zealand rabbits were used. Myocardial infarction was induced by left anterior descending artery ligation. A segment of uterus was removed via a laparotomy incision, and this uterine segment was transplanted as an autologous graft over the infarcted myocardium, which was then reinforced by greater omentum. Statistical methods and outcome measures Hemodynamic measurements and histological studies. Main findings: All uterine myometrial patches survived in the test animals. Fluoroscopic hemodynamic measurements were made for ejection fractions at 8 weeks after the application of the uterine patch. Histological study demonstrated well-healed myometrial-myocardium junctions with minimum scar tissue. Angiogenesis occurred in the transplanted myometrium. Connexin 43 expression was demonstrated in the transplanted patches. Conclusion Our noncontrolled preliminary rabbit experiments indicate that patches of uterine myometrium reinforced by greater omentum can be used as autologous transplant therapy for infracted myocardium. This is an innovative technique that could lead to future treatment for individuals who may suffer from an infarcted myocardium and may not be eligible for traditional reperfusion therapy.

Quantification of human epidermal growth factor receptor 2 immunohistochemistry using the Ventana Image Analysis System: correlation with gene amplification by fluorescence in situ hybridization: the importance of instrument validation for achieving high (>95%) concordance rate.

The use of computer-based image analysis for scoring human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) has gained a lot of interest recently. We investigated the performance of the Ventana Image Analysis System (VIAS) in HER2 quantification by IHC and its correlation with fluorescence in situ hybridization (FISH). We specifically compared the 3+ IHC results using the manufacturer’s machine score cutoffs versus laboratory-defined cutoffs with the FISH assay. Using the manufacturer’s 3+ cutoff (VIAS score; 2.51 to 3.5), 181/536 (33.7%) were scored 3+, and FISH was positive in 147/181 (81.2%), 2 (1.1%) were equivocal, and 32 (17.6%) were FISH (−). Using the laboratory-defined 3+ cutoff (VIAS score 3.5), 52 (28.7%) cases were downgraded to 2+, of which 29 (55.7%) were FISH (−), and 23 (44.2%) were FISH (+). With the revised cutoff, there were improvements in the concordance rate from 89.1% to 97.0% and in the positive predictive value from 82.1% to 97.6%. The false-positive rate for 3+ decreased from 9.0% to 0.8%. Six of 175 (3.4%) IHC (−) cases were FISH (+). Three cases with a VIAS score 3.5 showed polysomy of chromosome 17. In conclusion, the VIAS may be a valuable tool for assisting pathologists in HER2 scoring; however, the positive cutoff defined by the manufacturer is associated with a high false-positive rate. This study highlights the importance of instrument validation/calibration to reduce false-positive results.

Antinuclear Antibodies (ANA) and Complement Fixing ANA in Systemic Connective Tissue Diseases

Screening for antinuclear antibodies (ANA) with parallel tests for complement fixing ANA (C-ANA) reveal that C-ANA react either as strongly as or more strongly than ANA in most cases of systemic lupus erythematosus (SLE) and related disorders including CREST syndrome. But sera of drug induced LE and other ANA positive subjects have weak or no C-ANA. (P < 0.0005). Titrations with parallel C-ANA/ANA tests of two cases reveal primarily ANA and less C-ANA reactions in a case of drug induced LE but in CREST syndrome both ANA and C-ANA tests yield elevated titers with stronger C-ANA reactions. These findings point to distinct immunochemical mechanisms in C-ANA and ANA reactions.

The role of skin ulceration in breast carcinoma staging and outcome

Breast carcinoma with skin ulceration (SU) is considered a locally advanced disease. The purpose of the study is to investigate if SU is an independent adverse factor. Breast carcinoma patients with SU (n=111) were included in the study. A subset (n=38, study cohort) was matched with cases that had no SU (n=38, matched cohort); the survival analyses were compared between these groups. Then, cases (n=80) were staged independent from SU into stage I, II or III. Disease free survival (DFS) and overall survival (OS) were analyzed. Patients with larger tumors tended to present with distant metastases more often than patients with smaller tumors (P=.004). In the matched cases, the 5‐year DFS probability was 53% for the study cohort and 58% for the matched cohort; and for OS 75% for the study cohort and 84% for the matched cohort with no statistical significant difference. However, there was a trend towards worse DFS for the patients whose tumors had SU. When the cases were staged based on tumor size and node status (I, II or III), the OS was statistically significant (P=.047) but not the DFS (P=.195). Relatively small tumors with SU had an extent of disease similar to that observed in patients with early stages disease. The survival analysis suggests that SU may not be an adverse factor. However, more cases are needed to further examine this finding.

Pathology quiz case 1. Cemento-ossifying fibroma (COF).

A 16-YEAR-OLD GIRL PRESENTED WITH AN incidentally noted abnormality in the paranasal sinuses. Computed tomography revealed a soft-tissue mass in the right midanterior ethmoidal region and sphenoidal rostrum (Figure 1). There were also 2 separate right ethmoidal mucoceles and a single large sphenoidal mucocele, with evidence of sphenoidal expansion and erosion into the clivus. The skull base and lamina papyracea were intact. The patient reported some nasal congestion, frontal headaches, and 1 episode of mild epistaxis. She denied any vision changes. Endoscopic examination showed an erythematous mass in the right sphenoethmoidal recess. Nasal endoscopy with biopsy was performed. The biopsy specimen showed a mixture of spindled stroma with variable cellularity and well-formed bony trabeculae with noticeable osteoblastic rimming (Figure 2). Other areas with abundant, small, round to oval to irregular calcified ossicles resembling cementum with osteoid rimming were noted (Figure 3). What is your diagnosis?

Unusual Colon Polyps

C uestion: A 39-year-old Hispanic man with a 7-year istory of intermittent left lower quadrant abdominal ain and hematochezia. He is otherwise healthy. On everal computed tomography (CT) scans, there were iffuse colonic diverticula. During acute attacks, inflamatory changes were noted within the pelvis adjacent to large, inflamed, sigmoid diverticulum. These finings ere consistent with acute sigmoid diverticulitis. He was reated with antibiotics. During colonoscopy, there was ignificant sigmoid luminal narrowing with near circumerential erythematous and bluish mucosa (Figure A and ideo Clip) at 35 cm from the anal verge. This discolored ucosal segment was actually the base of several elonated and pedunculated polyps (Figure B). The pedicles f these polyps were hyperemic and adenomatous tissue as not observed. One of these pedunculated polyps was emoved through snare polypectomy uneventfully. What s the diagnosis? See the GASTROENTEROLOGY web site (www. astrojournal.org) for more information on submiting your favorite image to Clinical Challenges and mages in GI. SHOU-JIANG TANG, MD Department of Gastroenterology, Hepatology and Endoscopy Trinity Mother Frances Hospitals and Clinics Tyler, Texas YISHENG V. FANG, MD Department of Pathology The UT Southwestern Medical Center Dallas, Texas