Alexander Langerman

Integrative and Comparative Genomic Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas

Purpose: The genetic differences between human papilloma virus (HPV)–positive and –negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC. Experimental Design: We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% HPV-positive). Mutations and copy-number aberrations were determined and results validated with a secondary method. Results: The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus 14.4 somatic exonic mutations in the targeted cancer-associated genes. HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA, and NOTCH genes. HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3, and NOTCH1 were enriched in HPV-positive tumors. Currently targetable genomic alterations were identified in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA. EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, whereas 17.6% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes (FGFR2/3), including six recurrent FGFR3 S249C mutations. HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA-repair gene aberrations, including 7.8% BRCA1/2 mutations, were identified. Conclusions: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes. Clin Cancer Res; 21(3); 632–41. ©2014 AACR. See related commentary by Krigsfeld and Chung, p. 495

Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era

BACKGROUND Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors that are characterized by constitutive overexpression of the tyrosine kinase receptor KIT (CD117). Imatinib mesylate is a selective inhibitor of tyrosine kinase-mediated activity. This study reports a single-institution experience of surgical resection and the use of imatinib in the treatment of GIST. METHODS A retrospective review from 1995 to 2002 identified 57 patients (M:F, 29:28; median age, 61 years) with GIST who were treated at the University of Chicago. Twenty-eight patients underwent exploratory surgery with curative intent; 29 patients were referred for treatment of metastatic disease after surgery at outside institutions. Twenty-nine patients were treated with oral imatinib for either metastatic disease (n=26 patients) or in the adjuvant setting after complete resection (n=3 patients). RESULTS Resections were performed in 53 patients, and metastatic disease was identified in 17 patients at the time of exploratory surgery. Immunohistochemical staining for CD117 was positive in 96% of patients. A size larger than 5 cm, a mitotic rate larger than 1/10 high-power field, and tumor necrosis predicted recurrence in patients after resection. The median follow-up period was 18 months (range, 4-81 months). Twenty-three patients (40%) are alive without disease; 22 patients (39%) are alive with disease; 7 patients died, and 5 patients are lost to follow-up. Among the 26 patients with metastatic disease who were treated with imatinib, 5 deaths have occurred, and disease stabilization or tumor regression was observed initially in 22 patients, with a median duration of response of 19 months. CONCLUSIONS Complete surgical extirpation remains the only curative treatment of GIST. Imatinib-targeted therapy of metastatic disease yields encouraging clinical responses. The true efficacy of imatinib in this setting, as induction therapy or as an adjuvant treatment in patients with GIST, is unknown pending the completion of ongoing prospective trials.

Video Capture of Plastic Surgery Procedures Using the GoPro HERO 3

Background: Significant improvements can be made in recoding surgical procedures, particularly in capturing high-quality video recordings from the surgeons’ point of view. This study examined the utility of the GoPro HERO 3+ Black Edition camera for high-definition, point-of-view recordings of plastic and reconstructive surgery. Methods: The GoPro HERO 3+ Black Edition camera was head-mounted on the surgeon and oriented to the surgeon’s perspective using the GoPro App. The camera was used to record 4 cases: 2 fat graft procedures and 2 breast reconstructions. During cases 1-3, an assistant remotely controlled the GoPro via the GoPro App. For case 4 the GoPro was linked to a WiFi remote, and controlled by the surgeon. Results: Camera settings for case 1 were as follows: 1080p video resolution; 48 fps; Protune mode on; wide field of view; 16:9 aspect ratio. The lighting contrast due to the overhead lights resulted in limited washout of the video image. Camera settings were adjusted for cases 2-4 to a narrow field of view, which enabled the camera’s automatic white balance to better compensate for bright lights focused on the surgical field. Cases 2-4 captured video sufficient for teaching or presentation purposes. Conclusions: The GoPro HERO 3+ Black Edition camera enables high-quality, cost-effective video recording of plastic and reconstructive surgery procedures. When set to a narrow field of view and automatic white balance, the camera is able to sufficiently compensate for the contrasting light environment of the operating room and capture high-resolution, detailed video.

Utility of Lip Biopsy in the Diagnosis and Treatment of Sjogren's Syndrome

Objective: Sjogrens syndrome (SS) is an autoimmune disease involving primarily the salivary and lacrimal glands (“sicca” symptoms) with extraglandular features including joint and nervous system involvement. In patients with a questionable diagnosis of SS but severe extraglandular symptoms, a lip biopsy is often performed to firmly establish the diagnosis of SS. This study was undertaken to identify areas of uncertainty regarding the accuracy of biopsy interpretation and the diagnostic benefits of the procedure.

CD4 and CD8 T-lymphocyte recognition of prostate specific antigen in granulomatous prostatitis.

In order to develop immunotherapies for prostate cancer, many groups are exploring vaccination strategies to induce an immune response against prostate specific antigen (PSA). To determine if T-cell recognition of PSA might be a feature of a naturally occurring human disease, we have studied patients with prostatitis, a poorly understood clinical syndrome of men in which there is evidence that an immune response directed against the prostate may be occurring. We wished to determine if a T-cell response to PSA might be occurring in these patients. We generated long-term T-cell lines from peripheral blood mononuclear cells (PBMC) of one patient with granulomatous prostatitis using purified PSA as an antigen. Several CD4+ and CD8+ TcR &agr;/&bgr;+ T-cell lines were selected for PSA reactivity as measured by at least a threefold increase in IFN-&ggr; secretion in response to PSA presented by irradiated autologous PBMC. CD4 and CD8 T-cell lines recognized PSA in the context of HLA-DR&bgr;1*1501 and HLA-B*0702, respectively. The specificity and HLA restriction of the lines was confirmed using EBV-B cell lines infected with a recombinant PSA-expressing vaccinia virus and also engineered to express PSA by retroviral transfection. HLA-matched targets infected by control vector as well as HLA-mismatched PSA-expressing targets did not induce the response. The data demonstrate that PSA-specific T cells are present in the PBMC of this patient with granulomatous prostatitis, who may be manifesting naturally the type of immune response directed at the prostate that is the goal of prostate cancer immunotherapy. However, the Class I-restricted epitope has not yet been demonstrated to be expressed on the surface of prostate cancer cells. To our knowledge, this is the first demonstration of HLA-DRB1*1501- or HLA-B*0702-restricted responses to PSA and extends the number of HLA molecules accommodating the use of PSA antigen as a candidate vaccine for prostate cancer immunotherapy.

Assessing the Magnitude and Costs of Intraoperative Inefficiencies Attributable to Surgical Instrument Trays

BACKGROUND Efficiency in the operating room has become a topic of great interest. This study aimed to quantify the percent use of instruments among common instrument trays across 4 busy surgical services: Otolaryngology, Plastic Surgery, Bariatric Surgery, and Neurosurgery. We further aimed to calculate the costs associated with tray and instrument sterilization, as well as the implications of missing or damaged instruments. STUDY DESIGN This was a single-site, observational study conducted on the surgical instrumentation at a large academic medical center in Chicago. Data were collected through direct observation by a trained investigator. Operating room instrument use and labor time required for cleaning and repacking instrument trays in central sterile processing (CSP) were analyzed using descriptive statistics and linear regression. Institutional data on volume and expenses were gathered from hospital leadership. RESULTS Forty-nine procedures and 237 individual trays were observed. Average instrument (±SD)use rates were 13.0% for Otolaryngology (±4.2%), 15.5% for Plastic Surgery (±2.9%), 18.2% for Bariatric Surgery (±5.0%), and 21.9% for Neurosurgery (±1.7%). An increasing number of instruments per tray was associated with decreased use and increased instrument error rate. Using recorded labor time, the cost of cleaning and repackaging an individual instrument was calculated to be

Acute Fungal Sinusitis: Natural History and the Role of Frozen Section

0.10. Adding in CSP operating expenses and instrument depreciation per use, total processing cost per instrument increases to

The Minor Salivary Gland Biopsy as a Diagnostic Tool for Sjogren Syndrome

0.51 or more. CONCLUSIONS Our study demonstrates that the percent use of instruments across surgical specialties and multiple tray types is low. Attention to tray composition may result in immediate and significant cost savings.

Antibiotic and Duration of Perioperative Prophylaxis Predicts Surgical Site Infection in Head and Neck Surgery

Acute fungal sinusitis is a life-threatening infection affecting immunocompromised patients. Historically, the most commonly recovered fungi are Aspergillus and Mucor. The extent of potentially disfiguring debridement surgery is grossly determined by the appearance of bleeding at the margins, signifying viable tissue and the absence of fungus. Requests for frozen section may concern the initial diagnosis and the intraoperative verification of margin status. In 12 patients with acute fungal sinusitis, frozen section was used in 8. Routine H&E stains demonstrated fungal hyphae in necrotic debris in 5 cases, often associated with vascular and perineural invasion. All patients underwent extensive sinus debridement, including orbital exenteration in 2 cases. All 12 patients died, 9 of fungal sepsis. Autopsy in 3 patients showed pulmonary involvement (2 cases), intracranial spread (1 case), and no residual fungus (1 case). Inexperience with organism recognition is surmountable. Frozen section has a role in the management of this devastating disease.

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

In suspected cases of Sjogren syndome (SS), patients are often referred for a labial minor salivary gland biopsy. However, studies have shown this test to be unreliable. Pathologic misinterpretation and immunosuppressive medications may affect the results of the biopsy. As a result, it is best to perform this procedure only when necessary. The purpose of the current study was to review clinical signs and symptoms of patients who underwent a lip biopsy to determine which patients benefited most from this procedure.