James M. Lewis

Biomarkers Predict Outcomes Following Cytoreductive Surgery for Hepatic Metastases from Functional Carcinoid Tumors

BackgroundCytoreductive therapy for metastatic carcinoid provides symptomatic relief and improvement in overall survival. We evaluated whether CgA and 5HIAA could predict symptomatic relief and control of disease progression after cytoreductive surgery.MethodsWe retrospectively reviewed 70 patients who underwent cytoreductive surgery for neuroendocrine hepatic metastases between 1996 and 2005. Twenty-two patients had pre and post-operative CgA and/or 5HIAA levels measured. Reduction of biomarkers following cytoreduction was correlated with patient symptoms and progression of disease following surgery.ResultsOur study consisted of 14 males and 8 females with a mean age of 55 (±12 years). Median follow-up was 18 months (range 5-64 months). Six patients (26.1%) had complete (R0) cytoreduction, while 4 (17.4%) and 13 (56.5%) had microscopic (R1) and gross (R2) disease remaining. All patients reported improvements in their symptoms, with 12 (54.5%) reporting complete resolution (CR) and 10 (45.5%) reporting partial resolution (PR). Reduction of CgA of ≥ 80% was highly predictive of complete resolution of symptoms (P = 0.007) and stabilization of disease (P = 0.034). Reduction of 5HIAA levels of ≥ 80% (or normalization) was predictive of symptomatic relief, but not progression of disease (P = 0.026 and P = 0.725). Five of six patients who had R0 resections had CR and were free of disease at last follow-up (median 24.5 months, range: 11–48, P = 0.002).ConclusionsWe conclude that ≥ 80% reduction in CgA level following cytoreductive surgery for carcinoid tumors is predictive of subsequent symptom relief and disease control. Substantial reduction in CgA is associated with improved patient outcomes, even after incomplete cytoreduction.

Toxicities associated with hyperthermic isolated limb perfusion and isolated limb infusion in the treatment of melanoma and sarcoma

Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) may play a significant role in the treatment of patients with recurrent or in transit extremity melanoma or sarcoma that is unresectable. These procedures may be indicated when patients are otherwise faced with the possibility of a debilitating amputation. Not entirely benign treatment modalities, HILP and ILI can be associated with regional and systemic toxicities. We conducted a literature search of published studies using HILP and ILI for the treatment of extremity sarcomas and melanomas, and associated toxicities was performed. The regional toxicities of HILP and ILI are similar. The most common toxicities reported are mild to moderate. However, when severe regional toxicity occurs, albeit infrequently (<5%), fasciotomies or even amputation may be necessary. Some studies have showed a relationship between acute regional toxicities and long term regional morbidity. Systemic toxicity appears to be more frequent when TNF-α is used in combination with other drugs during HILP, however the use of TNF-α in the United States is limited to trials. Although regional toxicities are similar, systemic toxicity of ILI is minimal compared to HILP. ILI is easier to repeat, technically less complex, and may be more acceptable in infirmed patients. Long term morbidity and outcomes for ILI are still being evaluated. Both of these techniques may be suitable options in patients with unresectable advanced or recurrent, or in transit extremity melanoma or sarcoma.

Gene expression profiling of colorectal mucinous adenocarcinomas

PURPOSE: Although mucinous adenocarcinomas represent 6% to 19% of all colorectal adenocarcinomas, little is known about the genome-wide alterations associated with this malignancy. We have sought to characterize both the gene expression profiles of mucinous adenocarcinomas and their clinicopathologic features. METHODS: Tumors from 171 patients with primary colorectal cancer were profiled using the Affymetrix HG-U133Plus 2.0 GeneChip with characterization of clinicopathologic data. Gene ontology software was used to identify altered biologic pathways. RESULTS: Twenty (11.7%) mucinous adenocarcinomas and 151 (89.3%) nonmucinous adenocarcinomas were identified. Mucinous adenocarcinomas were more likely to be diagnosed with lymph node (LN) metastases (75% vs 51%, P = .04) and at a more advanced stage (85% vs 54%, P = .006) but long-term survival (5-y survival 58.9% vs 58.7%, P = NS) was similar. Mucinous adenocarcinomas displayed 182 upregulated and 135 downregulated genes. The most upregulated genes included those involved in cellular differentiation and mucin metabolism (eg, AQP3 + 4.6, MUC5AC +4.2, MUC2 + 2.8). Altered biologic pathways included those associated with mucin substrate metabolism (P = .002 and .02), amino acid metabolism (P = .02), and the mitogen-activated protein kinase cascade (P = .02). DISCUSSION: Using gene expression profiling of mucinous adenocarcinomas, we have identified the differential upregulation of genes involved in differentiation and mucin metabolism, as well as specific biologic pathways. These findings suggest that mucinous adenocarcinomas represent a genetically distinct variant of colorectal adencarcinoma and have implications for the development of targeted therapies.

Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling

BackgroundThe Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity. Herein we have extended these studies to the effects of ODAM on cultured melanoma cell lines.MethodsThe A375 and C8161 melanoma cell lines were stably transfected with ODAM and assayed for properties associated with tumorigenicity including cell growth, motility, and extracellular matrix adhesion. In addition, ODAM–transfected cells were assayed for signal transduction via AKT which promotes cell proliferation and survival in many neoplasms.ResultsODAM expression in A375 and C8161 cells strongly inhibited cell growth and motility in vitro, increased cell adhesion to extracellular matrix, and yielded significant cytoskeletal/morphologic rearrangement. Furthermore, AKT activity was downregulated by ODAM expression while an increase was noted in expression of the PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor gene, an antagonist of AKT activation. Increased PTEN in ODAM-expressing cells was associated with increases in PTEN mRNA levels and de novo protein synthesis. Silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing melanoma cells. Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN-deficient BT-549 breast cancer cells.ConclusionsThe apparent anti-neoplastic effects of ODAM in cultured melanoma and breast cancer cells are associated with increased PTEN expression, and suppression of AKT activity. This association should serve to clarify the clinical import of ODAM expression and any role it may serve as an indicator of tumor behavior.

Recurrent atypical fibroxanthoma with satellite metastasis

Atypical fibroxanthoma (AFX) is a cutaneous neoplasm of uncertain etiology that develops on sun‐exposed regions of elderly males. It is widely considered to act indolently, despite its highly malignant cytologic features. Reports of metastatic AFX are very rare, and recurrence is uncommon. We report a case of recurrent AFX exhibiting a pattern of satellite metastasis followed by evidence of regional lymph node metastasis. A 76‐year‐old male with prior occupational and therapeutic radiation exposure and numerous squamous cell carcinomas had AFX of the left vertex scalp limited to the dermis completely removed by micrographic surgery. Twenty months later, multiple lesions appeared at the site of previous surgery. Imaging revealed no metastases or calvarial involvement. Wide local excision showed multiple well‐defined nodules involving dermis and subcutis. The primary and recurrent neoplasms were similar and composed of pleomorphic epithelioid and spindled cells with marked nuclear atypia, hyperchromasia and mitotic activity. Immunohistochemistry was positive for CD10, procollagen1 and vimentin and negative for cytokeratins AE1/AE3, cytokeratins 5/6, 34βE12, MNF116, p63 CD31, Mart1, smooth muscle actin, desmin, S100 and CD34. Forty‐eight months after removal of the primary, left intraparotid and posterior triangle lymph nodes are suspected to be involved by metastasis using clinical and positron emission tomography/ computed tomography examinations.

Primary Cutaneous Melanoma Arising in a Long-Standing Irradiated Keloid

Ionizing radiation has been used therapeutically for a variety of clinical conditions, including treatment of hypertrophic keloids. Keloids may rarely be associated with malignancy, but the use of low-dose ionizing radiation is associated with an increased risk of cutaneous malignancies. We describe a case in which a primary desmoplastic melanoma arose in a long-standing, previously irradiated keloid.

Patterned Injury Analysis and Bitemark Comparison

Abstract The discipline of pattern recognition encompasses many forensic specialties including fingerprints, ballistics, and bitemarks. Recently, there have been criticisms of the use of these disciplines. Bitemarks, in particular, have come under intense scrutiny and some believe their use should be discontinued because they are not “scientific.” This chapter addresses these criticisms and discusses why bitemarks can be important pieces of evidence in violent encounters. It also puts into perspective how it has been misused and more importantly, its appropriate use.

Contralateral Prophylactic Mastectomy: Characteristics Influencing Utilization

Purpose: Breast conservation has been shown to have similar mortality rates as compared to mastectomy. We hypothesized that variables involving the patient, tumor and surgeon influence the treatment a patient may choose. Methods: Retrospective review of a prospectively maintained database of all patients who underwent surgical treatment for breast cancer between 2000 and 2009 was performed. Multivariate logistic regression models were used to compare characteristics associated with breast conservation therapy (BCT) and contralateral prophylactic mastectomy (CPM). Results: Of 1826 patients, 806 underwent BCT and 207 underwent CPM. Exclusion criteria included unilateral mastectomy (n=761), bilateral disease, stage IV disease, and incomplete records. Larger average tumor size and number of lymph nodes examined were associated with CPM (both p<0.0001). There were higher odds of patients who underwent CPM when younger than 40 (OR=3.1), less than 50 years of age (OR=2.5), with a history of breast cancer (OR=4.7), lobular histology (OR=2.3), invasive histology (OR=2.1), and multi-centric (OR=8.2). Patients treated by surgeons with greater than 10 years of experience were less than half as likely to undergo CPM (OR=0.4), however when treated by a surgeon not subspecialty trained in surgical oncology the patient was more likely to undergo CPM (OR=3.4). Conclusions: Our study is one of the first to evaluate patient comorbidities, personal history of breast cancer, and length of surgeon experience and the influence each may have on usage of CPM. Our data also suggest that there may be a training gap to bridge for general surgeons, because more surgery is becoming subspecialized.