Ryan K. Orosco

Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p and validates in HNSCC and pan-cancer cohorts. In human papillomavirus (HPV)-positive tumors, in which HPV inactivates TP53, 3p deletion is also common and is associated with poor outcomes. The TP53-3p event is modified by mir-548k expression, which decreases survival further, and is mutually exclusive with mutations affecting RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease.

Prediction of Mortality After Radical Prostatectomy by Charlson Comorbidity Index

OBJECTIVES Prostate cancer treatment should depend on the characteristics of a patients prostate cancer as well as overall health status. A possible adverse consequence of poor patient selection is a lack of benefit because of premature death from another cause. We evaluated the association between perioperative comorbidity and risk of death from causes other than prostate cancer in men who underwent radical prostatectomy (RP). METHODS We conducted a retrospective cohort study of 14,052 men who underwent RP from 1983 to 2006. The Charlson Comorbidity Index (CCI) score was calculated using the discharge records for the prostatectomy hospitalization. Mortality status and cause of death were obtained via chart review and searches of national databases. Cox proportional hazards regression was used to estimate the hazard ratio (HR) of death from causes other than prostate cancer after RP by CCI score (0, 1, 2+). RESULTS The median age at RP was 58.1 years. The median follow-up was 7.6 years (interquartile range 4.3-11.5). Of 849 deaths, 599 (70.6%) resulted from causes other than prostate cancer. On multivariable analysis, men with a CCI ≥2 had a statistically significantly higher risk of death from causes other than prostate cancer compared with those with lower CCI scores (HR 2.18, 95% CI 1.30-3.64, P = .0003). CONCLUSIONS Greater perioperative comorbidity was associated with a higher risk of death from causes other than prostate cancer in men who underwent RP. Physicians should consider using a standardized tool to assess perioperative comorbidities to enhance appropriate recommendation for surgical treatment.

Fluorescence Imaging in Surgery

Although the modern surgical era is highlighted by multiple technological advances and innovations, one area that has remained constant is the dependence of the surgeons vision on white-light reflectance. This renders different body tissues in a limited palette of various shades of pink and red, thereby limiting the visual contrast available to the operating surgeon. Healthy tissue, anatomic variations, and diseased states are seen as slight discolorations relative to each other and differences are inherently limited in dynamic range. In the upcoming years, surgery will undergo a paradigm shift with the use of targeted fluorescence imaging probes aimed at augmenting the surgical armamentarium by expanding the “visible” spectrum available to surgeons. Such fluorescent “smart probes” will provide real-time, intraoperative, pseudo-color, high-contrast delineation of both normal and pathologic tissues. Fluorescent surgical molecular guidance promises another major leap forward to improve patient safety and clinical outcomes, and to reduce overall healthcare costs. This review provides an overview of current and future surgical applications of fluorescence imaging in diseased and nondiseased tissues and focus on the innovative fields of image processing and instrumentation.

Failed exstrophy closure: Management and outcome

OBJECTIVE In a series of failed exstrophy closures, to identify determinants of successful repeat closure and the impact of failed closure on the fate of the lower urinary tract and continence status. PATIENTS AND METHODS We performed a retrospective review of operative notes and medical records of patients with a history of one or more failed exstrophy closures in 1978-2007. The primary surgical endpoints were failure rate of repeat closure attempts, mode of continence surgery and continence outcome. Continence was defined as achieving a dry interval of >3h and voiding through the urethra. RESULTS We identified 122 patients (85 male/37 female) who had undergone repeat closure following failure. The success rate of repeat closure attempts at our institution was 98%. Of the 94 patients who had undergone successful repeat closure, definitive continence management and had their dryness evaluated, 38 were candidates for bladder neck reconstruction and 17(18%) were continent. Of the remaining patients, 90% were able to attain dryness, but at the expense of clean intermittent catheterization and continent urinary diversion. CONCLUSION A failed exstrophy closure has significant implications for long-term surgical outcome. Reclosure can be accomplished in the majority of cases. In comparison to patients with successful primary closure, the rates of urethral continence following successful repeat closure were lower.

Analysis of Age and Disease Status as Predictors of Thyroid Cancer-Specific Mortality Using the Surveillance, Epidemiology, and End Results Database

BACKGROUND Age at diagnosis is incorporated into all relevant staging systems for differentiated thyroid carcinoma (DTC). There is growing evidence that a specific age cutoff may not be ideal for accurate risk stratification. We sought to evaluate the interplay between age and oncologic variables in patients with DTC using the largest cohort to date. METHODS The Surveillance, Epidemiology, and End RESULTS (SEER) database was queried to identify patients with DTC as their only malignancy for the period 1973 to 2009. Multivariate analyses using a range of age cutoffs and age subgroupings were utilized in order to search for an optimal age that would provide the most significant risk stratification between young and old patients. The primary outcome was disease-specific survival (DSS) and covariates included: age, race, sex, tumor/nodal/metastasis (TNM) stage, decade of diagnosis, and radioactive iodine therapy. RESULTS A total of 85,740 patients were identified. Seventy-six percent of patients were American Joint Committee on Cancer (AJCC) stage I, 8% were stage II, 7% were stage III, and 8% were stage IV. Age over 45 years (hazard ratio [HR] 19.2, p<0.001) and metastatic disease (HR 13.1, p<0.001) were the strongest predictors of DSS. Other factors that significantly predicted DSS included: not receiving radioactive iodine (RAI; HR 1.3, p=0.002), T3 (HR 2.6, p<0.001), and T4 disease (HR 3.3, p<0.001), and nodal spread (HR 2.6 to 3.3, p<0.001). Female sex showed a significant protective effect (HR 0.7, p=0.001). Adjusting the age-group cutoff from 25 to 55 years showed consistently high HRs for advanced age, without a distinct change at any point. Comparing HRs for T, N, and M stage between young and old patient subgroups showed that advanced disease increased the risk for DSS regardless of age, and was oftentimes a worse prognosticator in young patient groups. CONCLUSIONS The contribution of age at diagnosis to a patients DSS is considerable, but there is no age cutoff that affords any unique risk-stratification in patients with DTC.

Effect of failed initial closure on bladder growth in children with bladder exstrophy.

PURPOSE Failed initial bladder exstrophy closure may hinder the natural course of bladder growth compared to successful primary reconstruction. By measuring successive bladder capacities within the first 5 years of life, we compared the rate of bladder growth in children with failed vs successful initial closure. MATERIALS AND METHODS We used an approved bladder exstrophy database to identify and review retrospectively patients with classic bladder exstrophy who underwent repeat cystograms between ages 1 and 6 years. Two groups of patients were identified--those with successful neonatal closure (group 1) and those with successful reclosure after an initial failed procedure (group 2). A generalized linear mixed model was fit to evaluate the impact of treatment group and age on bladder growth. RESULTS We identified 48 patients in group 1 (75% male) and 62 in group 2 (71% male). Initial pelvic osteotomy was done in 60% of group 1 and 34% of group 2. Patients in group 1 had significantly larger cystographic capacity at 2, 4, 5 and 6 years after successful bladder closure compared to those in group 2 (p <0.05). The bladder tended to grow at a significantly slower rate in group 2 (9.38 cc yearly) compared to group 1 (14.76 cc yearly, p = 0.005). CONCLUSIONS Patients with initial failed bladder exstrophy closure showed significantly smaller cystographic capacities and slower bladder growth compared to those who underwent successful neonatal bladder closure. These data clearly underscore the importance of a secure, successful primary closure.

Lymph Node Yield as a Predictor of Survival in Pathologically Node Negative Oral Cavity Carcinoma.

Objective Even after a pathologically node-negative (pN0) neck dissection for oral cavity squamous cell carcinoma (SCC), patients may develop regional recurrence. In this study, we (1) hypothesize that an increased number of lymph nodes removed (lymph node yield) in patients with pN0 oral SCC predicts improved survival and (2) explore predictors of survival in these patients using a multivariable model. Study Design Case series with chart review. Setting Administrative database analysis. Subjects and Methods The SEER database was queried for patients diagnosed with all-stage oral cavity SCC between 1988 and 2009 who were determined to be pN0 after elective lymph node dissection. Demographic and treatment variables were extracted. The association of lymph node yield with 5-year all-cause survival was studied with multivariable survival analyses. Results A total of 4341 patients with pN0 oral SCC were included in this study. The 2 highest lymph node yield quartiles (representing >22 nodes removed) were found to be significant predictors of overall survival (22-35 nodes: hazard ratio [HR] = 0.854, P = .031; 36-98 nodes: HR = 0.827, P = .010). Each additional lymph node removed during neck dissection was associated with increased survival (HR = 0.995, P = .022). Conclusion These data suggest that patients with oral SCC undergoing elective neck dissection may experience an overall survival benefit associated with greater lymph node yield. Mechanisms behind the demonstrated survival advantage are unknown. Larger nodal dissections may remove a greater burden of microscopic metastatic disease, diminishing the likelihood of recurrence. Lymph node yield may serve as an objective measure of the adequacy of lymphadenectomy.

Matrix-Metalloproteinases in Head and Neck Carcinoma–Cancer Genome Atlas Analysis and Fluorescence Imaging in Mice

Objective (1) Obtain matrix-metalloproteinase (MMP) expression profiles for head and neck squamous cell carcinoma (HNSCC) specimens from the Cancer Genomic Atlas (TCGA). (2) Demonstrate HNSCC imaging using MMP-cleavable, fluorescently labeled ratiometric activatable cell-penetrating peptide (RACPP). Study Design Retrospective human cohort study; prospective animal study. Setting Translational research laboratory. Subjects and Methods Patient clinical data and mRNA expression levels of MMP genes were downloaded from TCGA data portal. RACPP provides complementary ratiometric fluorescent contrast (increased Cy5 and decreased Cy7 intensities) when cleaved by MMP2/9. HNSCC–tumor bearing mice were imaged in vivo after RACPP injection. Histology was evaluated by a pathologist blinded to experimental conditions. Zymography confirmed MMP-2/9 activity in xenografts. RACPP was applied to homogenized human HNSCC specimens, and ratiometric fluorescent signal was measured on a microplate reader for ex vivo analysis. Results Expression of multiple MMPs including MMP2/9 is greater in patient HNSCC tumors than matched control tissue. In patients with human papilloma virus positive (HPV+) tumors, higher MMP2 and MMP14 expression correlates with worse 5-year survival. Orthotopic tongue HNSCC xenografts showed excellent ratiometric fluorescent labeling with MMP2/9-cleavable RACPP (sensitivity = 95.4%, specificity = 95.0%). Fluorescence ratios were greater in areas of higher tumor burden (P < .03), which is useful for intraoperative margin assessment. Ex vivo, human HNSCC specimens showed greater cleavage of RACPP when compared to control tissue (P = .009). Conclusions Human HNSCC tumors show increased mRNA expression of multiple MMPs including MMP2/9. We used RACPP, a ratiometric fluorescence assay of MMP2/9 activity, to show improved occult tumor identification and margin clearance. Ex vivo assays using RACPP in biopsy specimens may identify patients who will benefit from intraoperative RACPP use.

Outcomes of isolated basilar skull fracture: Readmission, meningitis, and cerebrospinal fluid leak

Objective To determine rates of cerebrospinal fluid (CSF) leak, meningitis, and readmission in pediatric and adult patients with isolated basilar skull fracture. Study Design Cross-sectional analysis of a statewide database. Subjects Patients with isolated basilar skull fracture (1995-2010). Methods Patients were identified within the California Office of Statewide Health Planning and Development database using ICD-9 diagnosis codes. Results A total of 3563 pediatric and 10,761 adult patients met inclusion criteria. In-hospital rates of meningitis (0.48% and 0.64%, P = .3360) and CSF leak (2.33% and 1.75%, P = .0270) were similar among children and adults, respectively. Rates of 90-day meningitis (0.17% and 0.37%, P = .0714) and CSF leak (0.40% and 0.40%, P = .9823) were also similar. Thirty-day readmission was 4.6% for children compared with 12.4% for adults (P < .001). For both pediatric and adult patients, extra-axial hematoma (odds ratio [OR] [confidence interval {CI}] 1.65 [1.05-2.59] and 1.61 [1.34-1.95]) and comorbidities (OR [CI] 2.19 [1.11-4.34] and 1.28 [1.04-1.59]) were associated with significant increases in 30-day readmission. Loss of consciousness greater than 1 hour (OR, 3.05; 95% CI, 1.53-6.08) and CSF leak (OR, 3.28; 95% CI, 1.41-7.64) increased the likelihood of pediatric readmissions. Lack of insurance (OR, 0.67; 95% CI, 0.50-0.90) and female gender (OR 0.83; 95% CI, 0.70-0.99) reduced the likelihood of adult readmission. Conclusion Meningitis and CSF leak following isolated basilar skull fractures are uncommon. Readmission within 30 days was more common in adults than in children. CSF leak, hematoma, and prolonged loss of consciousness increased the likelihood of readmission in children. Intracranial injury, male gender, having insurance, and comorbidities increased the likelihood of readmission in adults.

Ambulatory Thyroidectomy A Multistate Study of Revisits and Complications

Objective Determine rates and reasons for revisits after ambulatory adult thyroidectomy. Study Design Cross-sectional analysis of multistate ambulatory surgery and hospital databases. Setting Ambulatory surgery data from the State Ambulatory Surgery Databases of California, Florida, Iowa, and New York for calendar years 2010 and 2011. Subjects and Methods Ambulatory thyroidectomy cases were linked to state ambulatory, emergency, and inpatient databases for revisit encounters occurring within 30 days. The numbers of revisits, mortality, and associated diagnoses were analyzed. Results A total of 25,634 cases of ambulatory thyroid surgery were identified: 44.2% total thyroidectomy (TT) and 55.8% partial thyroidectomy (PT). Common indications for surgery included goiter/cyst (39.5%), benign/uncertain neoplasm (24.2%), and malignant neoplasm (24.0%). The 30-day revisit rate was 7.2% (n = 1858; 61.8% emergency department, 22.4% inpatient admission, and 15.8% ambulatory surgery center). The most common diagnosis at revisit was hypocalcemia (20.8% of revisits), followed by wound hematoma/seroma/bleeding (7.1%). Higher rates of revisit, hypocalcemia, and hematoma/seroma/bleeding were seen in patients undergoing TT (P < .016 for all). Sixteen patients had bleeding less than 24 hours after the index procedure (0.1% overall, 0.9% of revisits). Most hypocalcemia and hematoma/bleeding occurred over the first postoperative week. Three deaths occurred within 30 days of the index procedure. Conclusion In carefully selected patients, ambulatory thyroidectomy demonstrates a good postoperative morbidity and mortality profile. Common reasons for revisits included hypocalcemia and bleeding/seroma/hematoma, which occurred with relatively high frequencies as late as a week after surgery. Quality improvement measures should be targeted at lowering revisit rates and safely managing complications.